Compound, production method therefor, and use of said compound

ABSTRACT

A compound expressed by any one of Structural Formulas (1) to (13), a method for producing the same, and a compound-containing composition, an anti-cancer agent, and an anti- Helicobacter pylori  agent each containing the above compound.

This application is a Continuation of U.S. patent application Ser. No.14/770,492, filed on Aug. 26, 2015, which is a National Phaseapplication under 35 U.S.C. 371 of International Application No.PCT/JP2014/054268, filed on Feb. 24, 2014, which claims priority toJapanese Application No. 2013-035732, filed on Feb. 26, 2013, all ofwhich are hereby incorporated by reference in their entireties.

TECHNICAL FIELD

The present invention relates to a novel compound, a method forproducing the same, and a composition, an anti-cancer agent, and ananti-Helicobacter pylori agent each containing the novel compound.

BACKGROUND ART

Tissue of cancer is not made from cancer cells only, but is made from amixture of cancer cells and their surrounding normal tissue calledstroma. The stroma is composed of a variety of factors such as bloodvessels, extracellular matrix, and fibroblast-like cells (hereinaftermay be referred to simply as “stromal cells”) and has been elucidated toclosely relate to proliferation of cancer. In particular, stromal cellsin the stroma are known to control proliferation of cancer cells bothpositively and negatively via adhesion and/or secretory components (see,for example, NPL 1). Under such circumstances, exploration has been madefor more useful, new anti-cancer agents, and it has been stronglydemanded to rapidly provide them.

In stomach and duodenal disorders such as stomach ulcer and duodenalulcer, some of them are known to be caused by Helicobacter pylori. Inview of this, quinolone compounds have been proposed as compounds havinganti-Helicobacter pylori activity (see, for example, NPL 2 and PTL 1).However, it cannot be said that the above proposed quinolone compoundsare satisfactory in use as a pharmaceutical drug, and it has beendemanded to provide new compounds having anti-Helicobacter pyloriactivity.

CITATION LIST Patent Literature

-   PTL 1: U.S. Pat. No. 5,942,619

Non-Patent Literature

-   NPL 1: Kawada, M., Inoue, H., Masuda, T., and Ikeda, D. Insulin-like    growth factor-I secreted from prostate stromal cells mediates    tumor-stromal cell interactions of the prostate cancer. Cancer Res.    66, 4419-4425 (2006).-   NPL 2: Dekker, K. A., Inagaki, T., Gootz, T. D., Huang, L. H.,    Kojima, Y., Kohlbrenner, W. E., Matsunaga, Y., McGuirk, P. R.,    Nomura, E., Sakakibara, T., Sakemi, S., Suzuki, Y., Yamauchi, Y.,    and Kojima, N. New quinolone compounds from Pseudonocardia sp. with    selective and potent anti-Helicobacter pylori activity: taxonomy of    producing strain, fermentation, isolation, structural elucidation    and biological activities. J. Antibiot. 51, 145-152 (1998).

SUMMARY OF INVENTION Technical Problem

The present invention has been made in view of the above existingtechnique, and aims to achieve the following object. That is, an objectof the present invention is to provide a novel compound having excellentanti-cancer effects or excellent anti-Helicobacter pylori activity, amethod for producing the novel compound, a compound-containingcomposition, anti-cancer agent, and anti-Helicobacter pylori agentutilizing the novel compound.

Solution to Problem

Means for solving the above problems are as follows.

<1> A compound expressed by any one of Structural Formulas (1) to (13)below:

where in the Structural Formulas (1) to (13), Me denotes a methyl group.

<2> A method for producing a compound expressed by any one of StructuralFormulas (3), (4), and (8) below, the method including:

reacting a compound expressed by any one of Structural Formula (17),(18), and (19) below with a hydroxide of an alkali metal or a hydroxideof an alkaline earth metal, or both thereof:

<3> A method for producing a compound expressed by Structural Formula(5) below, the method including:

reacting a compound expressed by Structural Formula (21) below with analkoxide of an alkali metal, a carbonic acid salt of an alkali metal ora hydride of an alkali metal, or any combination thereof, to therebyobtain a reaction product, and reacting the reaction product and methylbromoacetate:

where in the Structural Formula (5), Me denotes a methyl group.

<4> A method for producing a compound expressed by Structural Formula(6) below, the method including:

reacting a compound expressed by Structural Formula (5) below with ahydroxide of an alkali metal or a hydroxide of an alkaline earth metal,or both thereof, to thereby obtain a reaction product, and acidifying apH of the reaction product:

where in the Structural Formula (5), Me denotes a methyl group.

<5> A method for producing a compound expressed by Structural Formula(1) below, the method including:

reacting a compound expressed by Structural Formula (21) below with acarbonic acid salt of an alkali metal or a hydride of an alkali metal,or both thereof, and methyl bromoacetate:

where in the Structural Formula (1), Me denotes a methyl group.

<6> A method for producing a compound expressed by Structural Formula(2) below, the method including:

reacting a compound expressed by Structural Formula (1) below with ahydroxide of an alkali metal or a hydroxide of an alkaline earth metal,or both thereof, to thereby obtain a reaction product, and acidifying apH of the reaction product:

where in the Structural Formula (1), Me denotes a methyl group.

<7> A method for producing a compound expressed by Structural Formula(7) below, the method including:

reacting a compound expressed by Structural Formula (21) below with analkoxide of an alkali metal or a hydride of an alkali metal, or boththereof, to thereby obtain a reaction product, and reacting the reactionproduct and cyanogen bromide:

<8> A method for producing a compound expressed by Structural Formula(9) below, the method including:

reacting a compound expressed by Structural Formula (6) below with atertiary amine or a pyridine, or both thereof, diphenylphosphoryl azide,and sodium thiomethoxide:

where in the Structural Formula (9), Me denotes a methyl group.

<9> A method for producing a compound expressed by Structural Formula(10) below, the method including:

reacting a compound expressed by Structural Formula (6) below with atertiary amine or a pyridine, or both thereof, and diphenylphosphorylazide, to thereby obtain a reaction product, and reacting the reactionproduct and sodium thiomethoxide:

where in the Structural Formula (10), Me denotes a methyl group.

<10> A method for producing a compound expressed by Structural Formula(11) below, the method including:

reacting a compound expressed by Structural Formula (20) below with analkoxide of an alkali metal or a hydride of an alkali metal, or boththereof, to thereby obtain a reaction product, and reacting the reactionproduct and chloromethyl thiocyanate:

<11> A method for producing a compound expressed by Structural Formula(12) below, the method including:

reacting a compound expressed by Structural Formula (11) below withsodium thiomethoxide in the presence of acetonitrile:

where in the Structural Formula (12), Me denotes a methyl group.

<12> A method for producing a compound expressed by Structural Formula(13) below, the method including:

reacting a compound expressed by Structural Formula (11) below withsodium thiomethoxide in the presence of acetonitrile, to thereby obtaina reaction product, and reacting the reaction product and a methylatingagent:

where in the Structural Formula (13), Me denotes a methyl group.

<13> A compound-containing composition, including:

the compound according to <1>.

<14> An anti-cancer agent, including:

the compound according to <1>.

<15> An anti-Helicobacter pylori agent, including:

the compound according to <1>.

<16> A method for preventing or treating cancer, the method including:

administering the anti-cancer agent according to <14> to an individual.

<17> A method for preventing or treating an infectious disease caused byHelicobacter pylori, the method including:

administering the anti-Helicobacter pylori agent according to <15> to anindividual.

<18> A method for preventing or treating stomach and duodenal disorderscaused by Helicobacter pylori, the method including:

administering the anti-Helicobacter pylori agent according to <15> to anindividual.

Advantageous Effects of Invention

According to the present invention, it is possible to achieve the aboveobject and provide a novel compound having excellent anti-cancer effectsor excellent anti-Helicobacter pylori activity, a method for producingthe novel compound, a compound-containing composition, anti-canceragent, and anti-Helicobacter pylori agent utilizing the novel compound.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is a graph of changes in tumor volume in Test Example 2-1.

FIG. 1B is a graph of changes in tumor weight in Test Example 2-1 (Day21 from inoculation of tumor).

FIG. 1C is a graph of changes in tumor volume in Test Example 2-2.

FIG. 1D is a graph of changes in tumor weight in Test Example 2-2 (Day21 from inoculation of tumor).

DESCRIPTION OF EMBODIMENTS

(Novel Compound)

A compound of the present invention is a compound expressed by any oneof Structural Formulas (1) to (13) below, and is a novel compound foundby the present inventors.

In the above Structural Formulas (1) to (13), Me denotes a methyl group.

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (1)>

Physico-chemical properties of the compound expressed by StructuralFormula (1) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₂₉O₃N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 344.2221 (M+H)⁺.

Calcd: 344.2220 (as C₂₁H₃₀O₃N).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2953, 2925, 2854, 1765, 1618, 1596, 1437, 1123, 968,768, 680

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.6), 1.20-1.48 (10H, m), 1.71 (2H, m), 2.43 (3H, s),2.95 (2H, m), 3.86 (3H, s), 4.62 (2H, s), 7.47 (1H, ddd, J=8.2, 6.8,1.1), 7.62 (1H, ddd, J=8.4, 6.8, 1.3), 8.00 (1H, d, J=8.4), 8.05 (1H, d,J=8.2)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.90, 14.08, 22.63, 28.99, 29.23, 29.49, 29.86, 31.83, 37.02, 52.32,70.26, 120.85, 120.73, 121.39, 121.76, 125.73, 128.82, 128.85, 147.84,159.03, 164.32, 168.95

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (2)>

Physico-chemical properties of the compound expressed by StructuralFormula (2) as follows.

(1) Appearance: white powder

(2) Melting point: 59° C.-62° C.

(3) Molecular formula: C₂₀H₂₇O₃N

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 330.2064 (M+H)⁺.

Calcd: 330.2064 (as C₂₀H₂₈O₃N).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2927, 2855, 2713, 1736, 1642, 1589, 1227, 1181,1078, 764, 724

(6) Proton nuclear magnetic resonance spectrum (600 MHz, Methanol-d₄):

δ=0.88 (3H, t, J=6.8), 1.25-1.41 (8H, m), 1.50 (2H, m), 1.78 (2H, m),2.54 (3H, s), 3.15 (2H, t, m), 4.92 (2H, s), 7.54 (1H, ddd, J=8.2, 7.2,1.0), 7.92 (1H, ddd, J=8.5, 6.8, 1.0), 8.07 (1H, brd, J=8.5), 8.42 (1H,brd, J=8.2)

(7) ¹³C nuclear magnetic resonance spectrum (150 MHz, Methanol-d₄):

δ=12.23, 14.40, 23.67, 29.93, 30.27, 30.34, 30.74, 32.97, 35.07, 72.72,122.81, 123.71, 123.85, 124.62, 129.16, 133.85, 142.14, 164.30, 167.46,171.91

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (3)>

Physico-chemical properties of the compound expressed by StructuralFormula (3) as follows.

(1) Appearance: white powder

(2) Melting point: 178° C.-181° C.

(3) Molecular formula: C₁₉H₂₅ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 284.2011 (M+H)⁺.

Calcd: 284.2009 (as C₁₉H₂₆ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3064, 2957, 2933, 1670, 1638, 1614, 1555, 1500,1371, 1358, 1152, 1028, 998, 967, 756, 691

(6) Proton nuclear magnetic resonance spectrum (600 MHz, CDCl₃):

δ=0.95 (6H, d, J=6.5), 1.44 (2H, m), 1.69 (2H, m), 2.01 (2H, q, J=6.8),2.15 (3H, s), 2.21 (1H, m), 2.70 (2H, m), 5.27-5.32 (1H, m), 5.36-5.39(1H, m), 7.28 (1H, ddd, J=8.2, 5.8, 1.0), 7.32 (1H, brd, J=8.2), 7.52(1H, ddd, J=8.2, 5.5, 1.4), 8.36 (1H, dd, J=8.2, 1.4), 8.65 (1H, br)

(7) ¹³C nuclear magnetic resonance spectrum (150 MHz, CDCl₃):

δ=10.65, 22.64, 27.77, 29.22, 30.98, 32.09, 32.96, 115.72, 116.69,123.00, 123.66, 126.14, 126.30, 131.25, 138.49, 138.78, 148.54, 178.16

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (4)>

Physico-chemical properties of the compound expressed by StructuralFormula (4) as follows.

(1) Appearance: white powder

(2) Melting point: 240° C.-244° C.;

(3) Molecular formula: C₁₄H₁₇ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 216.1385 (M+H)⁺.

Calcd: 216.1383 (as C₁₄H₁₈ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3059, 2956, 1636, 1609, 1554, 1505, 1369, 1359,1189, 998, 762, 695

(6) Proton nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆):

δ=0.89 (6H, d, J=6.6), 1.94 (3H, s), 1.99 (1H, m), 2.53 (2H, d, J=7.5),7.18 (1H, ddd, J=8.2, 6.6, 1.4), 7.46 (1H, d, J=8.2), 7.52 (1H, ddd,J=8.2, 6.6, 1.4), 8.01 (1H, dd, J=8.2, 1.1), 11.23 (1H, br s)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, DMSO-d₆):

δ=11.03, 22.28, 28.30, 114.68, 117.74, 122.39, 123.00, 125.18, 131.08,139.33, 148.76, 176.43

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (5)>

Physico-chemical properties of the compound expressed by StructuralFormula (5) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₂₉O₃N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 344.2222 (M+H)⁺.

Calcd: 344.2220 (as C₂₁H₃₀O₃N).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2953, 2922, 1743, 1635, 1617, 1558, 1507, 1214, 994,760, 688

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.89 (3H, t, J=6.6), 1.21-1.51 (10H, m), 1.60 (2H, m), 2.22 (3H, s),2.74 (2H, br), 3.80 (3H, s), 4.90 (2H, s), 7.20 (1H, d, J=8.7), 7.33(1H, ddd, J=8.0, 6.8, 0.7), 7.58 (1H, ddd, J=8.7, 7.1, 1.6), 8.47 (1H,dd, J=8.0, 1.6)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.65, 14.06, 22.60, 28.06, 29.13, 29.17, 29.75, 30.93, 31.75, 48.47,53.01, 114.19, 117.55, 123.11, 124.79, 127.30, 131.89, 140.66, 150.66,168.69, 177.39

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (6)>

Physico-chemical properties of the compound expressed by StructuralFormula (6) as follows.

(1) Appearance: white powder

(2) Melting point: 161° C.-163° C.

(3) Molecular formula: C₂₀H₂₇O₃N

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 330.2063 (M+H)⁺.

Calcd: 330.2064 (as C₂₀H₂₈O₃N).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2955, 2925, 2853, 1725, 1635, 1593, 1506, 1191, 976,760, 689

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.4), 1.20-1.65 (12H, m), 2.19 (3H, s), 2.80 (2H, br),4.98 (2H, br), 7.26 (1H, t, J=8.0), 7.42 (1H, d, J=8.7), 7.54 (1H, ddd,J=8.7, 6.8, 1.1), 8.39 (1H, dd, J=8.0, 1.1)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.91, 14.06, 22.68, 27.85, 29.12, 29.78, 31.26, 31.73, 49.71, 115.46,117.21, 123.86, 123.94, 126.69, 132.47, 140.53, 154.22, 169.35, 176.57

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (7)>

Physico-chemical properties of the compound expressed by StructuralFormula (7) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₁₉H₂₄ON₂

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 297.1961 (M+H)⁺.

Calcd: 297.1961 (as C₁₉H₂₅ON₂).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2961, 2926, 2853, 2237, 1628, 1576, 1470, 1292,1191, 761, 693

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.8), 1.20-1.50 (10H, m), 1.71 (2H, m), 2.15 (3H, s),2.93 (2H, m), 7.47 (1H, m), 7.73 (2H, m), 8.33 (1H, ddd, J=8.0, 0.92,1.1)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.20, 14.05, 22.59, 28.00, 29.07, 29.11, 29.42, 31.73, 31.80, 106.42,116.28, 120.30, 123.35, 126.23, 127.08, 133.34, 137.25, 146.10, 177.31

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (8)>

Physico-chemical properties of the compound expressed by StructuralFormula (8) as follows.

(1) Appearance: yellow powder

(2) Melting point: >260° C.

(3) Molecular formula: C₁₈H₁₅ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 284.1046 (M+Na)⁺.

Calcd: 284.1046 (as C₁₈H₁₅ONNa).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3064, 2938, 1628, 1570, 1507, 1387, 1359, 1187, 965,755, 690

(6) Proton nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆):

δ=2.13 (3H, s), 7.21 (1H, ddd, J=8.5, 6.8, 1.1), 7.32-7.50 (5H, m),7.55-7.59 (1H, m), 7.67-7.72 (3H, m), 8.03 (1H, dd, J=8.2, 1.4), 11.20(1H,$)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, DMSO-d₆):

δ=10.66, 115.68, 118.18, 121.14, 122.55, 123.13, 125.14, 127.57, 129.16,129.30, 131.61, 135.11, 135.94, 139.75, 143.14, 176.76

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (9)>

Physico-chemical properties of the compound expressed by StructuralFormula (9) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₂₉O₂NS

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 360.1994 (M+H)⁺.

Calcd: 360.1992 (as C₂₁H₃₀O₂NS).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2924, 2852, 1687, 1614, 1594, 1542, 1193, 1028, 757,558

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.88 (3H, t, J=6.4), 1.20-1.50 (10H, m), 1.60 (2H, br), 2.23 (3H, s),2.33 (3H, s), 2.51-2.99 (2H, br), 5.01 (2H, br), 7.21 (1H, d, J=8.7),7.34 (1H, dd, J=8.0, 6.6), 7.58 (1H, ddd, J=8.7, 6.6, 1.4), 8.47 (1H,dd, J=8.0, 1.4)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.38, 11.68, 14.06, 22.60, 28.16, 29.13, 29.16, 29.75, 31.03, 31.74,55.95, 114.61, 117.94, 123.32, 127.29, 131.97, 132.02, 140.73, 150.65,177.49, 196.82

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (10)>

Physico-chemical properties of the compound expressed by StructuralFormula (10) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₃₀O₂N₂S

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 397.1921 (M+Na)⁺.

Calcd: 397.1920 (as C₂₁H₃₀O₂N₂NaS).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3169, 2955, 2927, 1671, 1615, 1595, 1556, 1492,1195, 1084, 760, 651

(5) Proton nuclear magnetic resonance spectrum (600 MHz, CDCl₃):

δ=0.89 (3H, t, J=6.7), 1.22-1.45 (15H, m), 2.45 (2H, br), 2.46 (3H, s),5.67 (2H, br), 7.24 (1H, ddd, J=7.9, 6.8, 1.0), 7.49 (1H, d, J=8.6),7.59 (1H, ddd, J=8.6, 6.8, 1.4), 8.26 (1H, dd, J=7.9, 1.4), 8.78 (1H,br)

(6) ¹³C nuclear magnetic resonance spectrum (150 MHz, CDCl₃):

δ=11.05, 12.22, 14.02, 22.59, 28.48, 29.11, 29.16, 29.73, 30.73, 31.77,52.58, 115.46, 117.00, 123.24, 124.37, 126.89, 132.32, 139.56, 151.60,168.61, 177.27

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (11)>

Physico-chemical properties of the compound expressed by StructuralFormula (11) as follows.

(1) Appearance: yellow oily substance

(2) Molecular formula: C₁₉H₂₄ON₂S

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 329.1682 (M+H)⁺.

Calcd: 329.1682 (as C₁₉H₂₅ON₂S).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2961, 2926, 2853, 2237, 1628, 1576, 1470, 1292,1191, 987, 761, 693

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.90 (3H, t, J=6.6), 1.23-1.71 (10H, m), 2.19 (3H, s), 2.84 (2H, m),5.71 (2H, s), 7.38 (1H, ddd, J=8.0, 6.8, 0.9), 7.46 (1H, d, J=8.7), 7.68(1H, ddd, J=8.7, 6.8, 1.6), 8.45 (1H, dd, J=8.0, 1.6)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.60, 14.05, 22.56, 28.59, 28.88, 29.76, 30.55, 31.66, 56.26, 114.42,118.19, 123.83, 124.60, 127.31, 132.41, 139.86, 141.68, 149.60, 177.64

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (12)>

Physico-chemical properties of the compound expressed by StructuralFormula (12) as follows.

(1) Appearance: yellow powder

(2) Melting point: 167° C.-170° C.

(3) Molecular formula: C₂₀H₂₈ON₂S₂

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 399.1534 (M+Na)⁺.

Calcd: 399.1535 (as C₂₀H₂₈ON₂NaS₂).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3119, 2958, 2918, 2850, 1619, 1598, 1538, 1282,1199, 1105, 938, 764, 688

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.86 (3H, t, J=6.6), 1.21-1.50 (13H, m), 2.22-2.58 (2H, br), 2.76 (3H,s), 5.68-6.41 (2H, br), 7.22 (1H, t, J=7.8), 7.44 (1H, d, J=8.7), 7.59(1H, ddd, J=8.7, 7.8, 1.1), 8.15 (1H, d, J=7.8), 10.09 (1H, br)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=10.74, 14.02, 18.01, 22.53, 28.29, 28.77, 29.64, 30.85, 31.59, 58.21,115.93, 116.84, 123.54, 123.91, 126.35, 132.65, 139.39, 152.23, 177.13,199.84

<Physico-Chemical Properties of the Compound Expressed by StructuralFormula (13)>

Physico-chemical properties of the compound expressed by StructuralFormula (13) as follows.

(1) Appearance: white powder

(2) Melting point: 92° C.-94° C.

(3) Molecular formula: C₂₁H₃₀ON₂S₂

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 413.1689 (M+Na)⁺.

Calcd: 413.1692 (as C₂₁H₃₀ON₂NaS₂).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2958, 2922, 2852, 1618, 1595, 1566, 1492, 1370,1277, 1192, 1004, 769, 700

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.89 (3H, t, J=6.8), 1.24-1.50 (8H, m), 1.64 (2H, m), 2.22 (3H, s),2.28 (3H, s), 2.71 (3H, s), 2.77 (2H, m), 5.60 (2H, s), 7.31 (2H, m),7.55 (1H, ddd, J=8.4, 7.1, 1.6), 8.46 (1H, dd, J=8.0, 1.6)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.50, 14.06, 14.75, 15.03, 22.61, 28.28, 28.92, 29.83, 30.66, 31.76,63.75, 115.84, 116.97, 122.77, 124.81, 126.75, 131.27, 141.06, 151.35,161.39, 177.54

Whether the above compound has a structure expressed by any one of theabove Structural Formulas (1) to (13) can be determined withappropriately selected various analysis methods. Examples thereofinclude spectroscopies such as the above mass spectrometry, the aboveinfrared spectroscopy, the above proton nuclear magnetic resonance, theabove ¹³C nuclear magnetic resonance, and ultraviolet spectroscopy. Notethat, the measurements obtained by each of the above analysis methodsmay have some errors, but those skilled in the art could easily identifywhich of the structures expressed by the above Structural Formulas (1)to (13) the compound has.

The above compound may be a salt of the compound expressed by any one ofthe above Structural Formulas (1) to (13).

The above salt is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is apharmacologically acceptable salt. Examples thereof include organicsalts such as acetic acid salts and citric acid salts, hydrochloric acidsalts, and carbonic acid salts.

The compound expressed by any one of the above Structural Formulas (1)to (13) may be a tautomer thereof.

A method for producing the compound expressed by any one of the aboveStructural Formulas (1) to (13) is not particularly limited and may beappropriately selected depending on the intended purpose. This compoundis preferably obtained by a production method of the present inventiondescribed below.

<Applications>

The compound expressed by any one of the above Structural Formulas (1)to (13) has excellent anti-cancer effects or excellent anti-Helicobacterpylori activity, and is a highly safe compound. Therefore, the compoundexpressed by any one of the above Structural Formulas (1) to (13) can besuitably used as an active ingredient of, for example, acompound-containing composition of the present invention, an anti-canceragent of the present invention, and an anti-Helicobacter pylori agent ofthe present invention, which will be described below.

(Method for Producing Compound)

<Method for Producing the Compound Expressed by any One of the AboveStructural Formulas (3), (4), and (8)>

A method for producing the compound expressed by any one of the aboveStructural Formulas (3), (4), and (8) is not particularly limited andmay be appropriately selected depending on the intended purpose so longas it is a method including reacting a compound expressed by any one ofStructural Formula (17), (18), and (19) below with a hydroxide of analkali metal or a hydroxide of an alkaline earth metal, or both thereof

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium. The alkaline earth metal refers to calcium,strontium, barium, and radium.

The above hydroxide of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include lithium hydroxide, sodium hydroxide, andpotassium hydroxide.

The above hydroxide of the alkaline earth metal is not particularlylimited and may be appropriately selected depending on the intendedpurpose. Examples thereof include barium hydroxide.

Either the above hydroxide of the alkali metal or the above hydroxide ofthe alkaline earth metal may be used, or both thereof may be used incombination.

One kind of the above hydroxide of the alkali metal may be used alone,or two or more kinds thereof may be used in combination. Also, one kindof the above hydroxide of the alkaline earth metal may be used alone, ortwo or more kinds thereof may be used in combination.

Among the above hydroxide of the alkali metal and the hydroxide of thealkaline earth metal, sodium hydroxide is preferable.

As preferable aspects of the method for producing the compound expressedby any one of the above Structural Formulas (3), (4), and (8), aspectswhere aminobenzonitrile is used as a starting material will be describedbelow.

——Production of the Compound Expressed by Structural Formula (14)——

The compound expressed by the above Structural Formula (14) can beproduced in the following manner, for example.

In an argon atmosphere, aminobenzonitrile is dissolved in anhydroustetrahydrofuran (hereinafter may be referred to as “THF”), andethylmagnesium bromide is added dropwise thereto in an ice bath. Themixture is stirred at room temperature for 12 hours, and thenhydrochloric acid aqueous solution (10%) is added dropwise thereto in anice bath. After completion of the dropwise addition, sodium hydroxide isadded thereto in an ice bath, and the pH of the mixture is adjusted to7. The organic layer is separated, and the aqueous layer is extractedwith diethyl ether. The organic layers are combined and dried withGlauber's salt, and the solvent is evaporated. The residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate=6:1), and as aresult the compound expressed by Structural Formula (14) can beobtained.

——Production of the Compound Expressed by Structural Formula (17)——

The compound expressed by the above Structural Formula (17) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) is dissolved in methylene chloride, and triethylamine isadded thereto. Furthermore, trans-8-methyl-6-nonenoyl chloride, which isan acid chloride, is added dropwise to the mixture in an ice bath,followed by stirring at room temperature. The reaction is terminatedwith 0.1N hydrochloric acid, and the mixture is extracted with methylenechloride, followed by washing with saturated sodium hydrogencarbonateaqueous solution and brine. The combined organic layer is dried withGlauber's salt, and then the solvent is evaporated. The residue ispurified through silica gel chromatography (hexane:ethyl acetate), andas a result the compound expressed by Structural Formula (17) can beobtained.

—Production of the Compound Expressed by Structural Formula (3)—

The compound expressed by the above Structural Formula (3) can beproduced in the following manner, for example.

Sodium hydroxide is added to a dioxane solution of the compoundexpressed by the above Structural Formula (17) (0.1 M), and the mixtureis stirred at 110° C. for 1 hour to 2 hours. The reaction solution isreturned to room temperature, followed by addition of water, and also,1N hydrochloric acid is added thereto until the pH thereof reaches 7.Furthermore, when hexane is added and then ultrasonic waves are appliedthereto, solids precipitate. The solids are filtrated throughaspiration, followed by washing with water, and hexane or a solventmixture of hexane/ethyl acetate=1:1. The washing is followed by drying,and as a result the compound expressed by Structural Formula (3) can beobtained.

——Production of the Compound Expressed by Structural Formula (18)——

The compound expressed by the above Structural Formula (18) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) is dissolved in methylene chloride, followed by addition oftriethylamine. Furthermore, isovaleryl chloride, which is an acidchloride, is added dropwise to the mixture in an ice bath, followed bystirring at room temperature. The reaction is terminated with 0.1Nhydrochloric acid, and the mixture is extracted with methylene chloride,followed by washing with saturated sodium hydrogencarbonate aqueoussolution and brine. The combined organic layer is dried with Glauber'ssalt, and then the solvent is evaporated. The residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate), and as aresult the compound expressed by Structural Formula (18) can beobtained.

—Production of the Compound Expressed by Structural Formula (4)—

The compound expressed by the above Structural Formula (4) can beproduced in the following manner, for example.

Sodium hydroxide is added to a 1,4-dioxane solution of the compoundexpressed by the above Structural Formula (18) (0.1 M), and the mixtureis stirred at 110° C. for 1 hour to 2 hours. The reaction solution isreturned to room temperature, followed by addition of water, and also,1N hydrochloric acid is added thereto until the pH thereof reaches 7.Furthermore, when hexane is added and ultrasonic waves are appliedthereto, solids precipitate. The solids are filtrated throughaspiration, followed by washing with water, and hexane or a solventmixture of hexane/ethyl acetate=1:1. The washing is followed by drying,and as a result the compound expressed by Structural Formula (4) can beobtained.

——Production of the Compound Expressed by Structural Formula (19)——

The compound expressed by the above Structural Formula (19) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) is dissolved in methylene chloride, followed by addition oftriethylamine. Furthermore, cinnamoyl chloride, which is an acidchloride, is added dropwise to the mixture in an ice bath, followed bystirring at room temperature. The reaction is terminated with 0.1Nhydrochloric acid, and the mixture is extracted with methylene chloride,followed by washing with saturated sodium hydrogencarbonate aqueoussolution and brine. The combined organic layer is dried with Glauber'ssalt, and then the solvent is evaporated. The residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate), and as aresult the compound expressed by Structural Formula (19) can beobtained.

—Production of the Compound Expressed by Structural Formula (8)—

The compound expressed by the above Structural Formula (8) can beproduced in the following manner, for example.

Sodium hydroxide is added to a 1,4-dioxane solution of the compoundexpressed by the above Structural Formula (19) (0.1 M), and the mixtureis stirred at 110° C. for 1 hour to 2 hours. The reaction solution isreturned to room temperature, followed by addition of water, and also,1N hydrochloric acid is added thereto until the pH thereof reaches 7.Furthermore, when hexane is added and ultrasonic waves are appliedthereto, solids precipitate. The solids are filtrated throughaspiration, followed by washing with water, and hexane or a solventmixture of hexane/ethyl acetate=1:1. The washing is followed by drying,and as a result the compound expressed by Structural Formula (8) can beobtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (5)>

A method for producing the compound expressed by the above StructuralFormula (5) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (21) belowwith an alkoxide of an alkali metal, a carbonic acid salt of an alkalimetal or a hydride of an alkali metal, or any combination thereof, tothereby obtain a reaction product, and reacting the reaction product andmethyl bromoacetate.

In the Structural Formula (5), Me denotes a methyl group.

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium.

The above alkoxide of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include lithium t-butoxide.

The above carbonic acid salt of the alkali metal is not particularlylimited and may be appropriately selected depending on the intendedpurpose. Examples thereof include sodium carbonate, potassium carbonate,sodium hydrogencarbonate, and potassium hydrogencarbonate.

The above hydride of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include sodium hydride.

One kind of the above alkoxide of the alkali metal, the above carbonicacid salt of the alkali metal, and the above hydride of the alkali metalmay be used alone, or two or more kinds thereof may be used incombination.

One kind of the above alkoxide of the alkali metal may be used alone, ortwo or more kinds thereof may be used in combination. One kind of theabove carbonic acid salt of the alkali metal may be used alone, or twoor more kinds thereof may be used in combination. Also, one kind of theabove hydride of the alkali metal may be used alone, or two or morekinds thereof may be used in combination.

Among the above alkoxide of the alkali metal, the above carbonic acidsalt of the alkali metal, and the above hydride of the alkali metal,lithium t-butoxide, potassium carbonate, and sodium hydride arepreferable, with lithium t-butoxide being more preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (5), an aspect where thecompound expressed by the above Structural Formula (14) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (14)can be suitably produced by the above-described method.

——Production of the Compound Expressed by Structural Formula (16)——

The compound expressed by the above Structural Formula (16) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) is dissolved in methylene chloride, and triethylamine isadded thereto. Furthermore, nonanoyl chloride, which is an acidchloride, is added dropwise to the mixture in an ice bath, followed bystirring at room temperature. The reaction is terminated with 0.1Nhydrochloric acid, and the mixture is extracted with methylene chloride,followed by washing with saturated sodium hydrogencarbonate aqueoussolution and brine. The combined organic layer is dried with Glauber'ssalt, and then the solvent is evaporated. The residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate), and as aresult the compound expressed by Structural Formula (16) can beobtained.

——Production of the Compound Expressed by Structural Formula (21)——

The compound expressed by the above Structural Formula (21) can beproduced in the following manner, for example.

Sodium hydroxide is added to a 1,4-dioxane solution of the compoundexpressed by the above Structural Formula (16) (0.1 M), and the mixtureis stirred at 110° C. for 1 hour to 2 hours. The reaction solution isreturned to room temperature, followed by addition of water, and also,1N hydrochloric acid is added thereto until the pH thereof reaches 7.Furthermore, when hexane is added and then ultrasonic waves are appliedthereto, solids precipitate. The solids are filtrated throughaspiration, followed by washing with water, and hexane or a solventmixture of hexane/ethyl acetate=1:1. The washing is followed by drying,and as a result the compound expressed by Structural Formula (21) can beobtained.

—Production of the Compound Expressed by Structural Formula (5)—

The compound expressed by the above Structural Formula (5) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (21) is dissolved in THF, and a THF solution of lithiumt-butoxide is added thereto, followed by stirring at room temperaturefor 20 minutes. Next, methyl bromoacetate is added thereto, and themixture is further stirred under reflux for 12 hours. The reaction isterminated by the addition of water, and the mixture is extracted withethyl acetate. The organic layer is dried with Glauber's salt, and thenthe solvent is evaporated. The residue is purified through silica gelchromatography (hexane:ethyl acetate=2:1), and as a result the compoundexpressed by Structural Formula (5) can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (6)>

A method for producing the compound expressed by the above StructuralFormula (6) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (5) belowwith a hydroxide of an alkali metal or a hydroxide of an alkaline earthmetal, or both thereof, to thereby obtain a reaction product, andacidifying a pH of the reaction product.

In the above Structural Formula (5), Me denotes a methyl group.

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium. The alkaline earth metal refers to calcium,strontium, barium, and radium.

The above hydroxide of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include lithium hydroxide, sodium hydroxide, andpotassium hydroxide.

The above hydroxide of the alkaline earth metal is not particularlylimited and may be appropriately selected depending on the intendedpurpose. Examples thereof include barium hydroxide.

Either the above hydroxide of the alkali metal or the above hydroxide ofthe alkaline earth metal may be used, or both thereof may be used incombination.

One kind of the above hydroxide of the alkali metal may be used alone,or two or more kinds thereof may be used in combination. Also, one kindof the above hydroxide of the alkaline earth metal may be used alone, ortwo or more kinds thereof may be used in combination.

Among the above hydroxide of the alkali metal and the hydroxide of thealkaline earth metal, sodium hydroxide is preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (6), an aspect where thecompound expressed by the above Structural Formula (5) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (5)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (6)—

The compound expressed by the above Structural Formula (6) can beproduced in the following manner, for example.

The Compound Expressed by the Above Structural Formula (5) is Dissolvedin a Solvent mixture of ethanol (hereinafter may be referred to as“EtOH”) and THF, and sodium hydroxide aqueous solution (2 M) is addedthereto, followed by stirring at room temperature for 2 hours. The pH ofthe mixture is adjusted to 4 by the addition of 1N hydrochloric acid inan ice bath, and the mixture is extracted with ethyl acetate. Theorganic layer is dried with Glauber's salt and the solvent isevaporated, and as a result the compound expressed by Structural Formula(6) can be obtained.

<Method for producing the compound expressed by the above StructuralFormula (1)>

A method for producing the compound expressed by the above StructuralFormula (1) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (21) belowwith a carbonic acid salt of an alkali metal or a hydride of an alkalimetal, or both thereof, and methyl bromoacetate.

In the above Structural Formula (1), Me denotes a methyl group.

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium.

The above carbonic acid salt of the alkali metal is not particularlylimited and may be appropriately selected depending on the intendedpurpose. Examples thereof include sodium carbonate, potassium carbonate,sodium hydrogencarbonate, and potassium hydrogencarbonate.

The above hydride of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include sodium hydride.

Either the above carbonic acid salt of the alkali metal or the abovehydride of the alkali metal may be used, or both thereof may be used incombination.

One kind of the above carbonic acid salt of the alkali metal may be usedalone, or two or more kinds thereof may be used in combination. Also,one kind of the above hydride of the alkali metal may be used alone, ortwo or more kinds thereof may be used in combination.

Among the above carbonic acid salt of the alkali metal and the abovehydride of the alkali metal, potassium carbonate and sodium hydride arepreferable, with potassium carbonate being more preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (1), an aspect where thecompound expressed by the above Structural Formula (21) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (21)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (1)—

The compound expressed by the above Structural Formula (1) can beproduced in the following manner, for example.

The compound expressed by the above Structural Formula (21) is dissolvedin N,N-dimethylformamide (hereinafter may be referred to as “DMF”), andpotassium carbonate and methyl bromoacetate are added thereto, followedby stirring at 80° C. for 12 hours. The reaction is terminated by theaddition of water, and the mixture is extracted with ethyl acetate. Theorganic layer is dried with Glauber's salt, and then the solvent isevaporated. The residue is purified through silica gel chromatography(hexane:ethyl acetate=2:1), and as a result the compound expressed byStructural Formula (1) can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (2)>

A method for producing the compound expressed by the above StructuralFormula (2) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (1) belowwith a hydroxide of an alkali metal or a hydroxide of an alkaline earthmetal, or both thereof, to thereby obtain a reaction product, andacidifying a pH of the reaction product.

In the above Structural Formula (1), Me denotes a methyl group.

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium. The alkaline earth metal refers to calcium,strontium, barium, and radium.

The above hydroxide of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include lithium hydroxide, sodium hydroxide, andpotassium hydroxide.

The above hydroxide of the alkaline earth metal is not particularlylimited and may be appropriately selected depending on the intendedpurpose. Examples thereof include barium hydroxide.

Either the above hydroxide of the alkali metal or the above hydroxide ofthe alkaline earth metal may be used, or both thereof may be used incombination.

One kind of the above hydroxide of the alkali metal may be used alone,or two or more kinds thereof may be used in combination. Also, one kindof the above hydroxide of the alkaline earth metal may be used alone, ortwo or more kinds thereof may be used in combination.

Among the above hydroxide of the alkali metal and the hydroxide of thealkaline earth metal, sodium hydroxide is preferable.

A method for acidifying the pH of the reaction product is notparticularly limited and may be appropriately selected depending on theintended purpose. Examples thereof include 1N hydrochloric acid.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (2), an aspect where thecompound expressed by the above Structural Formula (1) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (1)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (2)—

The compound expressed by the above Structural Formula (2) can beproduced in the following manner, for example.

The compound expressed by the above Structural Formula (1) is dissolvedin a solvent mixture of EtOH and THF, and sodium hydroxide aqueoussolution (2 M) is added thereto, followed by stirring at roomtemperature for 2 hours. The pH of the mixture is adjusted to 4 by theaddition of 1N hydrochloric acid in an ice bath, and the mixture isextracted with ethyl acetate. The organic layer is dried with Glauber'ssalt and the solvent is evaporated, and as a result the compoundexpressed by Structural Formula (2) can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (7)>

A method for producing the compound expressed by the above StructuralFormula (7) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (21) belowwith an alkoxide of an alkali metal or a hydride of an alkali metal, orboth thereof, to thereby obtain a reaction product, and reacting thereaction product and cyanogen bromide.

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium.

The above alkoxide of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include lithium t-butoxide.

The above hydride of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include sodium hydride.

Either the above alkoxide of the alkali metal or the above hydride ofthe alkali metal may be used, or both thereof may be used incombination.

One kind of the above alkoxide of the alkali metal may be used alone, ortwo or more kinds thereof may be used in combination. Also, one kind ofthe above hydride of the alkali metal may be used alone, or two or morekinds thereof may be used in combination.

Among the above alkoxide of the alkali metal and the above hydride ofthe alkali metal, lithium t-butoxide and sodium hydride are preferable,with lithium t-butoxide being more preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (7), an aspect where thecompound expressed by the above Structural Formula (21) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (21)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (7)—

The compound expressed by the above Structural Formula (7) can beproduced in the following manner, for example.

The compound expressed by the above Structural Formula (21) is dissolvedin THF, and lithium t-butoxide is added thereto, followed by stirring atroom temperature for 20 minutes. Next, cyanogen bromide is addedthereto, and the mixture is stirred at room temperature for 2 hours. Thereaction is terminated by the addition of water, and the mixture isextracted with ethyl acetate. The organic layer is dried with Glauber'ssalt, and then the solvent is evaporated. The residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate=2:1), and as aresult the compound expressed by Structural Formula (7) (34.0 mg, 62%)can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (9)>

A method for producing the compound expressed by the above StructuralFormula (9) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (6) belowwith a tertiary amine or a pyridine, or both thereof, diphenylphosphorylazide, and sodium thiomethoxide.

In the above Structural Formula (9), Me denotes a methyl group.

The tertiary amine is not particularly limited and may be appropriatelyselected depending on the intended purpose. Examples thereof includetriethylamine and N,N-diisopropylethylamine.

The pyridine is not particularly limited and may be appropriatelyselected depending on the intended purpose. Examples thereof includepyridine and dimethylaminopyridine.

Either the tertiary amine or the pyridine may be used, or both thereofmay be used in combination.

One kind of the tertiary amine may be used alone, or two or more kindsthereof may be used in combination. Also, one kind of the pyridine maybe used alone, or two or more kinds thereof may be used in combination.

Among the tertiary amine and the pyridine, triethylamine is preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (9), an aspect where thecompound expressed by the above Structural Formula (6) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (6)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (9)—

The compound expressed by the above Structural Formula (9) can beproduced in the following manner, for example.

The compound expressed by the above Structural Formula (6) is suspendedin THF, and triethylamine, diphenylphosphoryl azide (hereinafter may bereferred to as “DPPA”), and sodium thiomethoxide are added thereto, andthe mixture is stirred under reflux for 2 hours. Ammonium chlorideaqueous solution is added thereto, and the mixture is extracted withethyl acetate. The organic layer is dried with Glauber's salt, and thesolvent is evaporated. The residue is purified through silica gelchromatography (hexane:ethyl acetate=3:1), and as a result the compoundexpressed by Structural Formula (9) can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (10)>

A method for producing the compound expressed by the above StructuralFormula (10) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (6) belowwith a tertiary amine or a pyridine, or both thereof, anddiphenylphosphoryl azide, to thereby obtain a reaction product, andreacting the reaction product and sodium thiomethoxide.

In the above Structural Formula (10), Me denotes a methyl group.

The tertiary amine is not particularly limited and may be appropriatelyselected depending on the intended purpose. Examples thereof includetriethylamine and N,N-diisopropyl ethyl amine.

The pyridine is not particularly limited and may be appropriatelyselected depending on the intended purpose. Examples thereof includepyridine and dimethylaminopyridine.

Either the tertiary amine or the pyridine may be used, or both thereofmay be used in combination.

One kind of the tertiary amine may be used alone, or two or more kindsthereof may be used in combination. Also, one kind of the pyridine maybe used alone, or two or more kinds thereof may be used in combination.

Among the tertiary amine and the pyridine, triethylamine is preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (10), an aspect where thecompound expressed by the above Structural Formula (6) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (6)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (10)—

The compound expressed by the above Structural Formula (10) can beproduced in the following manner, for example.

The compound expressed by the above Structural Formula (6) is suspendedin THF, and triethylamine and DPPA are added thereto under cooling withice, and the mixture is further stirred under reflux for 1 hour. Sodiumthiomethoxide is added thereto, followed by stirring for another 1 hour.Ammonium chloride aqueous solution is added thereto, and the mixture isextracted with ethyl acetate. The organic layer is dried with Glauber'ssalt, and the solvent is evaporated. The residue is purified throughsilica gel chromatography (hexane:ethyl acetate=5:1), and as a resultthe compound expressed by Structural Formula (10) can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (11)>

A method for producing the compound expressed by the above StructuralFormula (11) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (20) belowwith an alkoxide of an alkali metal or a hydride of an alkali metal, orboth thereof, to thereby obtain a reaction product, and reacting thereaction product and chloromethyl thiocyanate.

The above alkali metal refers to lithium, sodium, potassium, rubidium,cesium, and francium.

The above alkoxide of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include lithium t-butoxide.

The above hydride of the alkali metal is not particularly limited andmay be appropriately selected depending on the intended purpose.Examples thereof include sodium hydride.

Either the above alkoxide of the alkali metal or the above hydride ofthe alkali metal may be used, or both thereof may be used incombination.

One kind of the above alkoxide of the alkali metal may be used alone, ortwo or more kinds thereof may be used in combination. Also, one kind ofthe above hydride of the alkali metal may be used alone, or two or morekinds thereof may be used in combination.

Among the above alkoxide of the alkali metal and the above hydride ofthe alkali metal, lithium t-butoxide and sodium hydride are preferable,with lithium t-butoxide being more preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (11), an aspect where thecompound expressed by the above Structural Formula (14) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (14)can be suitably produced by the above-described method.

——Production of the Compound Expressed by Structural Formula (15)——

The compound expressed by the above Structural Formula (15) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) is dissolved in methylene chloride, and triethylamine isadded thereto. Furthermore, octanoyl chloride, which is an acidchloride, is added dropwise to the mixture in an ice bath, followed bystirring at room temperature. The reaction is terminated with 0.1Nhydrochloric acid, and the mixture is extracted with methylene chloride,followed by washing with saturated sodium hydrogencarbonate aqueoussolution and brine. The combined organic layer is dried with Glauber'ssalt, and then the solvent is evaporated. The residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate), and as aresult the compound expressed by Structural Formula (15) can beobtained.

——Production of the Compound Expressed by Structural Formula (20)——

The compound expressed by the above Structural Formula (20) can beproduced in the following manner, for example.

Sodium hydroxide is added to a dioxane solution of the compoundexpressed by the above Structural Formula (15) (0.1 M), and the mixtureis stirred at 110° C. for 1 hour to 2 hours. The reaction solution isreturned to room temperature, followed by addition of water, and also,1N hydrochloric acid is added thereto until the pH thereof reaches 7.Furthermore, when hexane is added and ultrasonic waves are appliedthereto, solids precipitate. The solids are filtrated throughaspiration, followed by washing sequentially with water, and hexane or asolvent mixture of hexane/ethyl acetate=1:1. The washing is followed bydrying, and as a result the compound expressed by Structural Formula(20) can be obtained.

—Production of the Compound Expressed by Structural Formula (11)—

The compound expressed by the above Structural Formula (11) can beproduced in the following manner, for example.

In an argon atmosphere, the compound expressed by the above StructuralFormula (20) is dissolved in THF, and a THF solution of lithiumt-butoxide is added thereto, followed by stirring at room temperaturefor 20 minutes. Chloromethyl thiocyanate is added dropwise thereto undercooling with ice, followed by further stirring at room temperature for 2hours. The reaction is terminated by the addition of brine, and themixture is extracted with ethyl acetate. The organic layer is dried withGlauber's salt, and then the residue is purified through silica gelchromatography (hexane:ethyl acetate=2:1), and as a result the compoundexpressed by Structural Formula (11) is obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (12)>

A method for producing the compound expressed by the above StructuralFormula (12) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (11) belowwith sodium thiomethoxide in the presence of acetonitrile.

In the above Structural Formula (12), Me denotes a methyl group.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (12), an aspect where thecompound expressed by the above Structural Formula (11) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (11)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (12)—

The compound expressed by the above Structural Formula (12) can beproduced in the following manner, for example.

Acetonitrile is added to a mixture of the compound expressed by theabove Structural Formula (11) and sodium thiomethoxide, followed bystirring at room temperature for 20 minutes. Saturated sodiumhydrogencarbonate aqueous solution is added thereto, and the mixture isextracted with ethyl acetate. The organic layer is dried with Glauber'ssalt, and then the residue is purified through silica gel chromatography(hexane:ethyl acetate=2:1), and as a result the compound expressed byStructural Formula (12) can be obtained.

<Method for Producing the Compound Expressed by the Above StructuralFormula (13)>

A method for producing the compound expressed by the above StructuralFormula (13) is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as it is a methodincluding reacting a compound expressed by Structural Formula (11) belowwith sodium thiomethoxide in the presence of acetonitrile, to therebyobtain a reaction product, and reacting the reaction product and amethylating agent.

In the above Structural Formula (13), Me denotes a methyl group.

The methylating agent is not particularly limited and may beappropriately selected depending on the intended purpose. Examplesthereof include iodomethane, methyl trifluoromethanesulfonate, dimethylsulfate, and Meerwein reagents. One kind of the above methylating agentmay be used alone, or two or more kinds thereof may be used incombination. Among them, iodomethane is preferable.

As a preferable aspect of the method for producing the compoundexpressed by the above Structural Formula (13), an aspect where thecompound expressed by the above Structural Formula (11) is used as astarting material will be described below.

Note that, the compound expressed by the above Structural Formula (11)can be suitably produced by the above-described method.

—Production of the Compound Expressed by Structural Formula (13)—

The compound expressed by the above Structural Formula (13) can beproduced in the following manner, for example.

Acetonitrile is added to a mixture of the compound expressed by theabove Structural Formula (11) and sodium thiomethoxide, followed bystirring at room temperature for 20 minutes. Methyl iodide is addedthereto at room temperature, and the mixture is further stirred for 30minutes. Saturated sodium hydrogencarbonate aqueous solution is addedthereto, and the mixture is extracted with ethyl acetate. The organiclayer is dried with Glauber's salt, and then the residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate=2:1), and as aresult the compound expressed by Structural Formula (13) can beobtained.

Reaction conditions, compounds to be used, amounts thereof, solvents,and the like in the production method for each of the compoundsexpressed by the above structural formulas are not particularly limitedand may be appropriately selected depending on the intended purpose solong as the effects of the present invention are not impaired.

Whether each of the above compounds has a structure expressed by each ofthe above structural formulas can be determined with appropriatelyselected various analysis methods. Examples thereof includespectroscopies such as the above mass spectrometry, the aboveultraviolet spectroscopy, the above infrared spectroscopy, the aboveproton nuclear magnetic resonance, and the above ¹³C nuclear magneticresonance.

(Compound-Containing Composition, Anti-Cancer Agent, andAnti-Helicobacter-Pylori Agent)

<Compound-Containing Composition>

A compound-containing composition of the present invention contains atleast the compound expressed by any one of the above Structural Formulas(1) to (13); and, if necessary, further contains other ingredients.

One kind of the compound expressed by any one of the above StructuralFormulas (1) to (13) may be used alone, or two or more kinds thereof maybe used in combination.

An amount of the compound expressed by any one of the above StructuralFormulas (1) to (13) contained in the compound-containing composition isnot particularly limited and may be appropriately selected depending onthe intended purpose. The above compound-containing composition may bethe compound itself expressed by any one of the above StructuralFormulas (1) to (13).

—Other Ingredients—

The above other ingredients are not particularly limited and may beappropriately selected depending on the intended purpose frompharmacologically acceptable carriers. Examples thereof includeadditives, supplements and water. These may be used alone or incombination of two or more thereof.

The above additives or supplements are not particularly limited and maybe appropriately selected depending on the intended purpose. Examplesthereof include a disinfectant, a preserving agent, a binding agent, athickener, an adhesive agent, an integrating agent, a colorant, astabilizer, a pH adjuster, a buffer, a tonicity agent, a solvent, anantioxidant, a UV rays-preventing agent, a preventing agent forprecipitation of crystals, a defoaming agent, a property improving agentand an antiseptic agent.

The above disinfectant is not particularly limited and may beappropriately selected depending on the intended purpose. Examplesthereof include cationic surfactants such as benzalkonium chloride,benzethonium chloride and cetylpyridinium chloride.

The above preserving agent is not particularly limited and may beappropriately selected depending on the intended purpose. Examplesthereof include p-hydroxybenzoate esters, chlorobutanol and clesol.

The above binding agent, thickener and adhesive agent are notparticularly limited and may be appropriately selected depending on theintended purpose. Examples thereof include starch, dextrin, cellulose,methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyol cellulose, hydroxypropyolmethyl cellulose,carboxymethyl starch, pullulan, sodium alginate, ammonium alginate,propylene glycol alginic acid esters, guar gum, locust bean gum, gumArabic, xanthane gum, gelatin, casein, polyvinyl alcohol, polyethyleneoxide, polyethylene glycol, ethylene/propylene block polymers, sodiumpolyacrylates and polyvinylpyrrolidone.

The above integrating agent is not particularly limited and may beappropriately selected depending on the intended purpose. Examples ofthe integrating agent include water, ethanol, propanol, simple syrup,glucose liquid, starch liquid, gelatin liquid, carboxymethyl cellulose,hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethylcellulose, shellac, calcium phosphate and polyvinylpyrrolidone.

The above colorant is not particularly limited and may be appropriatelyselected depending on the intended purpose. Examples thereof includetitanium oxide and iron oxide.

The above stabilizer is not particularly limited and may beappropriately selected depending on the intended purpose. Examplesthereof include tragacanth, gum Arabic, gelatin, sodium pyrosulfite,ethylenediaminetetraacetate (EDTA), thioglycolic acid and thiolacticacid.

The above pH adjuster or the buffer is not particularly limited and maybe appropriately selected depending on the intended purpose. Examplesthereof include sodium citrate, sodium acetate and sodium phosphate.

The above tonicity agent is not particularly limited and may beappropriately selected depending on the intended purpose. Examplesthereof include sodium chloride and glucose.

An amount of the above other ingredients in the compound-containingcomposition is not particularly limited and may be appropriatelyselected depending on the intended purpose so long as the effects of thecompound expressed by any one of the above Structural Formulas (1) to(13) are not impaired.

—Applications—

Since the above compound-containing composition contains the compoundexpressed by any one of the above Structural Formulas (1) to (13), ithas excellent anti-cancer effects, excellent anti-Helicobacter pyloriactivity, and high safety, and can be suitably used for a pharmaceuticalcomposition, an anti-cancer agent, an anti-Helicobacter pylori agent,and the like.

Note that, the above compound-containing composition may be used aloneor in combination with a pharmaceutical drug containing anotheringredient as an active ingredient. Also, the above compound-containingcomposition may be used in a state of being formulated into apharmaceutical drug containing another ingredient as an activeingredient.

<Anti-Cancer Agent>

An anti-cancer agent of the present invention contains at least thecompound expressed by the above Structural Formulas (1) to (13); and, ifnecessary, further contains other ingredients.

One kind of the compound expressed by any one of the above StructuralFormulas (1) to (13) may be used alone, or two or more kinds thereof maybe used in combination.

An amount of the compound expressed by any one of the above StructuralFormulas (1) to (13) contained in the above anti-cancer agent is notparticularly limited and may be appropriately selected depending on theintended purpose. The above anti-cancer agent may be the compound itselfexpressed by any one of the above Structural Formulas (1) to (13).

—Other Ingredients—

The above other ingredients are not particularly limited and may beappropriately selected depending on the intended purpose frompharmacologically acceptable carriers. Examples thereof include thosesimilar to the other ingredients described for the abovecompound-containing composition. These may be used alone or incombination of two or more thereof.

An amount of the above other ingredients in the anti-cancer agent is notparticularly limited and may be appropriately selected depending on theintended purpose so long as the effects of the compound expressed by anyone of the above Structural Formulas (1) to (13) are not impaired.

—Applications—

Since the above anti-cancer agent contains the compound expressed by anyone of the above Structural Formulas (1) to (13), it has excellentanti-cancer effects and high safety, and can be suitably used as apreventive agent or a therapeutic agent for a wide range of cancers suchas stomach cancer, prostate cancer, lung cancer, colon cancer,pancreatic cancer, and breast cancer. Among them, it can be particularlysuitably used for stomach cancer and colon cancer.

Note that, the above anti-cancer agent may be used alone or incombination with a pharmaceutical drug containing another ingredient asan active ingredient. Also, the above anti-cancer agent may be used in astate of being formulated into a pharmaceutical drug containing anotheringredient as an active ingredient.

Also, as presented in the below-described Test Examples, the compoundexpressed by the above Structural Formulas (1) to (13) of the presentinvention can more suppress proliferation of cancer cells in thepresence of normal stromal cells.

Since the above anti-cancer agent contains the compound expressed by anyone of the above Structural Formulas (1) to (13), it can preventdevelopment of cancer in an individual or treat an individual sufferingfrom cancer by being administered to the individual. Therefore, thepresent invention also relates to a method for preventing or treatingcancer, including administering the above anti-cancer agent to anindividual.

<Anti-Helicobacter pylori Agent>

An anti-Helicobacter pylori agent of the present invention contains atleast the compound expressed by any one of the above Structural Formulas(1) to (13); and, if necessary, further contains other ingredients.

One kind of the compound expressed by any one of the above StructuralFormulas (1) to (13) may be used alone, or two or more kinds thereof maybe used in combination.

An amount of the compound expressed by any one of the above StructuralFormulas (1) to (13) contained in the anti-Helicobacter pylori agent isnot particularly limited and may be appropriately selected depending onthe intended purpose. The above anti-Helicobacter pylori agent may bethe compound itself expressed by any one of the above StructuralFormulas (1) to (13).

—Other Ingredients—

The above other ingredients are not particularly limited and may beappropriately selected depending on the intended purpose frompharmacologically acceptable carriers. Examples thereof include thosesimilar to the other ingredients described for the abovecompound-containing composition. These may be used alone or incombination of two or more thereof.

An amount of the above other ingredients in the anti-Helicobacter pyloriis not particularly limited and may be appropriately selected dependingon the intended purpose so long as the effects of the compound expressedby any one of the above Structural Formulas (1) to (13) are notimpaired.

—Applications—

Since the above anti-Helicobacter pylori agent contains the compoundexpressed by any one of the above Structural Formulas (1) to (13), ithas excellent anti-Helicobacter pylori activity and high safety, and canbe suitably used as a preventive agent or a therapeutic agent forstomach and duodenal disorders such as stomach ulcer and duodenal ulcer.

Note that, the above anti-Helicobacter pylori agent may be used alone orin combination with a pharmaceutical drug containing another ingredientas an active ingredient. Also, the above anti-Helicobacter pylori agentmay be used in a state of being formulated into a pharmaceutical drugcontaining another ingredient as an active ingredient.

Since the above anti-Helicobacter pylori agent contains the compoundexpressed by any one of the above Structural Formulas (1) to (13), itcan prevent an individual from being infected with Helicobacter pylorior treat an individual infected with Helicobacter pylori by beingadministered to the individual. Therefore, the present invention alsorelates to a method for preventing or treating an infectious diseasecaused by Helicobacter pylori including administering the aboveanti-Helicobacter pylori agent to an individual.

Also, the above anti-Helicobacter pylori agent can prevent developmentof stomach and duodenal disorders caused by Helicobacter pylori or treatan individual suffering from stomach and duodenal disorders caused byHelicobacter pylori by being administered to the individual. Therefore,the present invention also relates to a method for preventing ortreating stomach and duodenal disorders caused by Helicobacter pylori,including administering the above anti-Helicobacter pylori agent to anindividual.

<Dosage Form>

The above dosage form of the above compound-containing composition,anti-cancer agent, and anti-Helicobacter pylori agent is notparticularly limited and may be appropriately selected depending on theintended purpose. Examples thereof include a solid preparation, asemi-solid preparation and a liquid preparation. The abovecompound-containing composition, anti-cancer agent, andanti-Helicobacter pylori agent having any of these dosage forms can beproduced according to a routine method.

—Solid Preparation—

The above solid preparation is not particularly limited and may beappropriately selected depending on the intended purpose. When it isused as an internal preparation, examples of the solid preparationinclude tablets, chewable tablets, foaming tablets,orally-disintegrating tablets, troches, drops, hard capsules, softcapsules, granules, powder, pills, dry syrups and infusions.

When the above solid preparation is an external preparation, examples ofthe solid preparation include suppositories, cataplasms and plasters.

—Semi-Solid Preparation—

The above semi-solid preparation is not particularly limited and may beappropriately selected depending on the intended purpose. When it isused as an internal preparation, examples of the semi-solid preparationinclude electuaries, chewing gums, whip and jelly.

When the above semi-solid preparation is used as an externalpreparation, examples of the semi-solid preparation include ointments,cream, mousse, inhaler and nasal gel.

—Liquid Preparation—

The above liquid preparation is not particularly limited and may beappropriately selected depending on the intended purpose. When it isused as an internal preparation, examples of the liquid preparationinclude syrups, drinks, suspensions and spirits.

When the above liquid preparation is used as an external preparation,examples of the liquid preparation include liquid, eye drops, aerosoland sprays.

<Administration>

An administration method, an administration dose, an administrationperiod and an administration target of the above compound-containingcomposition, anti-cancer agent, and anti-Helicobacter pylori agent arenot particularly limited and may be appropriately selected depending onthe intended purpose.

Examples of the above administration method include a localadministration method, an enteral administration method and a parenteraladministration method.

The above administration dose is not particularly limited and may beappropriately selected considering various factors of an administrationtarget, such as the age, body weight, constitution, symptom and thepresence or absence of administration of a pharmaceutical drug or amedicament containing another ingredient as an active ingredient.

Animal species serving as the above administration target is notparticularly limited and may be appropriately selected depending on theintended purpose. Examples thereof include human, monkey, pig, bovine,sheep, goat, dog, cat, mouse, rat and bird. Among them, they can besuitably used for human.

EXAMPLES

The present invention will next be described in detail by way ofProduction Examples and Test Examples. However, the present invention isnot construed as being limited to these Production Examples and TestExamples.

Note that, data in the following Test Examples are representative onesfrom 2 or 3 independent experiments in which similar results wereobtained. Statistical analysis was performed based on the Student'st-test.

Production Example 1

<Production of the Compound Expressed by Structural Formula (3)>

In the following manner, the compound expressed by the above StructuralFormula (3) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (14)—

In an argon atmosphere, aminobenzonitrile (15.0 g, 128 mmol) wasdissolved in 300 mL of anhydrous tetrahydrofuran (hereinafter may bereferred to as “THF”), and ethylmagnesium bromide (127 mL, 383 mmol) wasadded dropwise thereto in an ice bath. The mixture was stirred at roomtemperature for 12 hours, and then hydrochloric acid aqueous solution(10%) (100 mL) was added dropwise thereto in an ice bath. Aftercompletion of the dropwise addition, sodium hydroxide was added theretoin an ice bath, and the pH of the mixture was adjusted to 7. The organiclayer was separated, and the aqueous layer was extracted with diethylether. The organic layers were combined and dried with Glauber's salt,and the solvent was evaporated. The residue was purified through silicagel chromatography (hexane:ethyl acetate=6:1), and as a result thecompound expressed by Structural Formula (14) (9.7 g, 51%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (14) as follows.

(1) Appearance: yellow powder

(2) Melting point: 42° C.-43° C.

(3) Molecular formula: C₉H₁₁ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 150.0911 (M+H)⁺.

Calcd: 150.0913 (as C₉H₁₂ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3434, 3331, 1644, 1620

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=1.21 (3H, q, J=7.3), 2.98 (2H, q, J=7.3), 6.27 (2H, br s), 6.62-6.67(2H, m), 7.25 (1H, ddd, J=7.3, 5.0, 1.4), 7.76 (1H, dd, J=8.7, 1.4)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=8.70, 32.27, 115.70, 117.30, 117.84, 131.10, 134.05, 150.21, 203.33

—Production of the Compound Expressed by Structural Formula (17)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) (1 equivalent) was dissolved in methylene chloride, andtriethylamine (2 equivalents) was added thereto. Furthermore,trans-8-methyl-6-nonenoyl chloride (1.1 equivalents), which is an acidchloride, was added dropwise to the mixture in an ice bath, followed bystirring at room temperature. The reaction was terminated with 0.1Nhydrochloric acid, and the mixture was extracted with methylenechloride, followed by washing with saturated sodium hydrogencarbonateaqueous solution and brine. The combined organic layer was dried withGlauber's salt, and then the solvent was evaporated. The residue waspurified through silica gel chromatography (hexane:ethyl acetate), andas a result the compound expressed by Structural Formula (17) wasobtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (17) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₁₉H₂₇O₂N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 324.1932 (M+Na)⁺.

Calcd: 324.1934 (as C₁₉H₂₇O₂NNa).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3255, 2956, 2937, 1655, 969, 754

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.95 (6H, d, J=6.8), 1.22 (3H, t, J=7.1), 1.44 (2H, m), 1.75 (2H, m),2.02 (2H, m), 2.22 (1H, m), 2.44 (2H, t, J=7.3), 3.07 (2H, q, J=7.1),5.37 (2H, m), 7.09 (1H, ddd, J=8.0, 7.3, 1.1), 7.53 (1H, ddd, J=8.5,7.3, 1.4), 7.92 (1H, dd, J=8.0, 1.4), 8.77 (1H, dd, J=8.5, 1.1), 11.77(1H, br s)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=8.45, 22.64, 25.03, 29.17, 30.96, 32.21, 33.14, 38.66, 120.84, 121.38,122.14, 126.50, 130.65, 134.84, 138.03, 141.06, 172.68, 205.36

—Production of the Compound Expressed by Structural Formula (3)—

Sodium hydroxide (3.0 equivalents) was added to a 1,4-dioxane solutionof the compound expressed by the above Structural Formula (17) (1equivalent) (0.1 M), and the mixture was stirred at 110° C. for 1 hourto 2 hours. The reaction solution was returned to room temperature,followed by addition of water, and also, 1N hydrochloric acid was addedthereto until the pH thereof reached 7. Furthermore, when hexane wasadded and ultrasonic waves were applied thereto, solids precipitated.The solids were filtrated through aspiration, followed by washingsequentially with water, hexane, and a solvent mixture of hexane/ethylacetate=1:1. The washing was followed by drying, and as a result thecompound expressed by Structural Formula (3) was obtained

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (3) as follows.

(1) Appearance: white powder

(2) Melting point: 178° C.-181° C.

(3) Molecular formula: C₁₉H₂₅ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 284.2011 (M+H)⁺.

Calcd: 284.2009 (as C₁₉H₂₆ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3064, 2957, 2933, 1670, 1638, 1614, 1555, 1500,1371, 1358, 1152, 1028, 998, 967, 756, 691

(6) Proton nuclear magnetic resonance spectrum (600 MHz, CDCl₃):

δ=0.95 (6H, d, J=6.5), 1.44 (2H, m), 1.69 (2H, m), 2.01 (2H, q, J=6.8),2.15 (3H, s), 2.21 (1H, m), 2.70 (2H, m), 5.27-5.32 (1H, m), 5.36-5.39(1H, m), 7.28 (1H, ddd, J=8.2, 5.8, 1.0), 7.32 (1H, brd, J=8.2), 7.52(1H, ddd, J=8.2, 5.5, 1.4), 8.36 (1H, dd, J=8.2, 1.4), 8.65 (1H, br)

(7) ¹³C nuclear magnetic resonance spectrum (150 MHz, CDCl₃):

δ=10.65, 22.64, 27.77, 29.22, 30.98, 32.09, 32.96, 115.72, 116.69,123.00, 123.66, 126.14, 126.30, 131.25, 138.49, 138.78, 148.54, 178.16

Production Example 2

<Production of the Compound Expressed by Structural Formula (4)>

In the following manner, the compound expressed by the above StructuralFormula (4) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (18)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) (1 equivalent) was dissolved in methylene chloride,followed by addition of triethylamine (2 equivalents). Furthermore,isovaleryl chloride (1.1 equivalents), which is an acid chloride, wasadded dropwise to the mixture in an ice bath, followed by stirring atroom temperature. The reaction was terminated with 0.1N hydrochloricacid, and the mixture was extracted with methylene chloride, followed bywashing with saturated sodium hydrogencarbonate aqueous solution andbrine. The combined organic layer was dried with Glauber's salt, andthen the solvent was evaporated. The residue was purified through silicagel chromatography (hexane:ethyl acetate), and as a result the compoundexpressed by Structural Formula (18) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (18) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₁₄H₁₉O₂N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 256.1306 (M+Na)⁺.

Calcd: 256.1308 (as C₁₄H₁₉O₂NNa).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3254, 2959, 1697, 1376, 754

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=1.01 (6H, d, J=6.4), 1.22 (3H, t, J=7.1), 2.24 (1H, m), 2.31 (2H, d,J=6.4), 3.07 (2H, q, J=7.1), 7.10 (1H, ddd, J=8.4, 6.8, 1.1), 7.53 (1H,ddd, J=8.5, 6.8, 1.4), 7.93 (1H, dd, J=8.0, 1.4), 8.78 (1H, d, J=8.5),11.75 (1H, br s)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=8.45, 22.46, 26.20, 33.15, 48.09, 120.81, 121.38, 122.16, 130.59,134.85, 141.02, 172.14, 205.40

—Production of the Compound Expressed by Structural Formula (4)—

Sodium hydroxide (3.0 equivalents) was added to a 1,4-dioxane solutionof the compound expressed by the above Structural Formula (18) (1equivalent) (0.1 M), and the mixture was stirred at 110° C. for 1 hourto 2 hours. The reaction solution was returned to room temperature,followed by addition of water, and also, 1N hydrochloric acid was addedthereto until the pH thereof reached 7. Furthermore, when hexane wasadded and ultrasonic waves were applied thereto, solids precipitated.The solids were filtrated through aspiration, followed by washingsequentially with water, hexane, and a solvent mixture of hexane/ethylacetate=1:1. The washing was followed by drying, and as a result thecompound expressed by Structural Formula (4) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (4) as follows.

(1) Appearance: white powder

(2) Melting point: 240° C.-244° C.;

(3) Molecular formula: C₁₄H₁₇ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 216.1385 (M+H)⁺.

Calcd: 216.1383 (as C₁₄H₁₈ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3059, 2956, 1636, 1609, 1554, 1505, 1369, 1359,1189, 998, 762, 695

(6) Proton nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆):

δ=0.89 (6H, d, J=6.6), 1.94 (3H, s), 1.99 (1H, m), 2.53 (2H, d, J=7.5),7.18 (1H, ddd, J=8.2, 6.6, 1.4), 7.46 (1H, d, J=8.2), 7.52 (1H, ddd,J=8.2, 6.6, 1.4), 8.01 (1H, dd, J=8.2, 1.1), 11.23 (1H, br s)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, DMSO-d₆):

δ=11.03, 22.28, 28.30, 114.68, 117.74, 122.39, 123.00, 125.18, 131.08,139.33, 148.76, 176.43

Production Example 3

<Production of the Compound Expressed by Structural Formula (8)>

In the following manner, the compound expressed by the above StructuralFormula (8) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (19)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) (1 equivalent) was dissolved in methylene chloride,followed by addition of triethylamine (2 equivalents). Furthermore,cinnamoyl chloride (1.1 equivalents), which is an acid chloride, wasadded dropwise to the mixture in an ice bath, followed by stirring atroom temperature. The reaction was terminated with 0.1N hydrochloricacid, and the mixture was extracted with methylene chloride, followed bywashing with saturated sodium hydrogencarbonate aqueous solution andbrine. The combined organic layer was dried with Glauber's salt, andthen the solvent was evaporated. The residue was purified through silicagel chromatography (hexane:ethyl acetate), and as a result the compoundexpressed by Structural Formula (19) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (19) as follows.

(1) Appearance: white powder

(2) Melting point: 109° C.-111° C.

(3) Molecular formula: C₁₈H₁₇O₂N

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 302.1151 (M+Na)⁺.

Calcd: 302.1152 (as C₁₈H₁₇O₂NNa).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3223, 3023, 1677, 1653, 751, 727

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=1.25 (3H, t, J=7.1), 3.11 (2H, q, J=7.1), 6.65 (1H, d, J=15.5), 7.13(1H, ddd, J=8.0, 7.1, 1.1), 7.36-7.44 (3H, m), 7.56-7.62 (3H, m), 7.76(1H, d, J=15.5), 7.96 (1H, dd, J=8.0, 1.4), 8.91 (1H, dd, J=8.5, 1.4),12.10 (1H, br s)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=8.43, 33.15, 121.06, 121.47, 122.09, 122.41, 128.07, 128.83, 129.95,130.69, 134.66, 134.93, 141.25, 142.25, 164.85, 205.56

—Production of the Compound Expressed by Structural Formula (8)—

Sodium hydroxide (3.0 equivalents) was added to a 1,4-dioxane solutionof the compound expressed by the above Structural Formula (19) (1equivalent) (0.1 M), and the mixture was stirred at 110° C. for 1 hourto 2 hours. The reaction solution was returned to room temperature,followed by addition of water, and also, 1N hydrochloric acid was addedthereto until the pH thereof reached 7. Furthermore, when hexane wasadded and ultrasonic waves were applied thereto, solids precipitated.The solids were filtrated through aspiration, followed by washingsequentially with water and hexane. The washing was followed by drying,and as a result the compound expressed by Structural Formula (8) wasobtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (8) as follows.

(1) Appearance: yellow powder

(2) Melting point: >260° C.

(3) Molecular formula: C₁₈H₁₅ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 284.1046 (M+Na)⁺.

Calcd: 284.1046 (as C₁₈H₁₅ONNa).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3064, 2938, 1628, 1570, 1507, 1387, 1359, 1187, 965,755, 690

(6) Proton nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆):

δ=2.13 (3H, s), 7.21 (1H, ddd, J=8.5, 6.8, 1.1), 7.32-7.50 (5H, m),7.55-7.59 (1H, m), 7.67-7.72 (3H, m), 8.03 (1H, dd, J=8.2, 1.4), 11.20(1H,$)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, DMSO-d₆):

δ=10.66, 115.68, 118.18, 121.14, 122.55, 123.13, 125.14, 127.57, 129.16,129.30, 131.61, 135.11, 135.94, 139.75, 143.14, 176.76

Production Example 4

<Production of the Compound Expressed by Structural Formula (5)>

In the following manner, the compound expressed by the above StructuralFormula (5) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (16)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) (1 equivalent) was dissolved in methylene chloride, andtriethylamine (2 equivalents) was added thereto. Furthermore, nonanoylchloride (1.1 equivalents), which is an acid chloride, was addeddropwise to the mixture in an ice bath, followed by stirring at roomtemperature. The reaction was terminated with 0.1N hydrochloric acid,and the mixture was extracted with methylene chloride, followed bywashing with saturated sodium hydrogencarbonate aqueous solution andbrine. The combined organic layer was dried with Glauber's salt, andthen the solvent was evaporated. The residue was purified through silicagel chromatography (hexane:ethyl acetate), and as a result the compoundexpressed by Structural Formula (16) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (16) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₁₈H₂₇O₂N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 312.1933 (M+Na)⁺.

Calcd: 312.1934 (as C₁₈H₂₇O₂NNa).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3255, 2953, 2928, 1698, 754

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.6), 1.20-1.41 (13H, m), 1.74 (2H, m), 2.43 (2H, t,J=7.6), 3.08 (2H, q, J=7.3), 7.09 (1H, ddd, J=8.0, 7.3, 1.1), 7.53 (1H,ddd, J=8.5, 7.3, 1.6), 7.93 (1H, dd, J=8.0, 1.6), 8.77 (1H, dd, J=8.5,1.1), 11.76 (1H, br s)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=8.54, 14.07, 22.63, 25.55, 29.14, 29.22, 29.28, 31.87, 33.20, 38.80,120.85, 121.96, 122.12, 130.57, 134.84, 141.08, 172.80, 205.37

—Production of the Compound Expressed by Structural Formula (21)—

Sodium hydroxide (3.0 equivalents) was added to a 1,4-dioxane solutionof the compound expressed by the above Structural Formula (16) (1equivalent) (0.1 M), and the mixture was stirred at 110° C. for 1 hourto 2 hours. The reaction solution was returned to room temperature,followed by addition of water, and also, 1N hydrochloric acid was addedthereto until the pH thereof reached 7. Furthermore, when hexane wasadded and ultrasonic waves were applied thereto, solids precipitated.The solids were filtrated through aspiration, followed by washing withwater and hexane. The washing was followed by drying, and as a resultthe compound expressed by Structural Formula (21) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (21) as follows.

(1) Appearance: white powder

(2) Melting point: 228° C.-231° C.

(3) Molecular formula: C₁₈H₂₅ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 272.2010 (M+H)⁺.

Calcd: 272.2009 (as C₁₈H₂₆ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3059, 2952, 2923, 1638, 1607, 1555, 1500, 1190, 998,754, 693

(6) Proton nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆):

δ=0.80 (3H, t, J=6.6), 1.19-1.35 (10H, m), 1.59 (2H, m), 1.94 (3H, s),2.62 (2H, t, J=7.5), 7.18 (1H, dd, J=8.2, 6.6), 7.45 (1H, d, J=8.0),7.51 (1H, ddd, J=8.2, 6.7, 1.4), 8.00 (1H, dd, J=8.0, 1.4), 11.31 (1H,br s)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, DMSO-d₆):

δ=10.48, 14.15, 22.26, 28.49, 28.80, 28.92, 29.04, 31.43, 31.84, 113.87,117.73, 122.39, 123.06, 125.18, 131.05, 139.36, 149.82, 176.39

—Production of the compound expressed by Structural Formula (5)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (21) (800 mg, 2.95 mmol) was dissolved in THF (20 mL), and a THFsolution of lithium t-butoxide (4.4 mL, 4.42 mmol) was added thereto,followed by stirring at room temperature for 20 minutes. Next, methylbromoacetate (1.4 mL, 14.7 mmol) was added thereto, and the mixture wasfurther stirred under reflux for 12 hours. The reaction was terminatedby the addition of water, and the mixture was extracted with ethylacetate. The organic layer was dried with Glauber's salt, and then thesolvent was evaporated. The residue was purified through silica gelchromatography (hexane:ethyl acetate=2:1), and as a result the compoundexpressed by Structural Formula (5) (780 mg, 76%1 was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (5) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₂₉O₃N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 344.2222 (M+H)⁺.

Calcd: 344.2220 (as C₂₁H₃₀O₃N).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2953, 2922, 1743, 1635, 1617, 1558, 1507, 1214, 994,760, 688

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.89 (3H, t, J=6.6), 1.21-1.51 (10H, m), 1.60 (2H, m), 2.22 (3H, s),2.74 (2H, br), 3.80 (3H, s), 4.90 (2H, s), 7.20 (1H, d, J=8.7), 7.33(1H, ddd, J=8.0, 6.8, 0.7), 7.58 (1H, ddd, J=8.7, 7.1, 1.6), 8.47 (1H,dd, J=8.0, 1.6)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.65, 14.06, 22.60, 28.06, 29.13, 29.17, 29.75, 30.93, 31.75, 48.47,53.01, 114.19, 117.55, 123.11, 124.79, 127.30, 131.89, 140.66, 150.66,168.69, 177.39

Production Example 5

<Production of the Compound Expressed by Structural Formula (6)>

In the following manner, the compound expressed by the above StructuralFormula (6) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (6)—

The compound expressed by the above Structural Formula (5) (890 mg, 2.59mmol) was dissolved in a solvent mixture of ethanol (hereinafter may bereferred to as “EtOH”, 5 mL) and THF (5 mL), and sodium hydroxideaqueous solution (2 M) (2.0 mL) was added thereto, followed by stirringat room temperature for 2 hours. The pH of the mixture was adjusted to 4by the addition of 1N hydrochloric acid in an ice bath, and the mixturewas extracted with ethyl acetate. The organic layer was dried withGlauber's salt and the solvent was evaporated, and as a result thecompound expressed by Structural Formula (6) (530 mg, 62%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (6) as follows.

(1) Appearance: white powder

(2) Melting point: 161° C.-163° C.

(3) Molecular formula: C₂₀H₂₇O₃N

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 330.2063 (M+H)⁺.

Calcd: 330.2064 (as C₂₀H₂₈O₃N).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2955, 2925, 2853, 1725, 1635, 1593, 1506, 1191, 976,760, 689

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.4), 1.20-1.65 (12H, m), 2.19 (3H, s), 2.80 (2H, br),4.98 (2H, br), 7.26 (1H, t, J=8.0), 7.42 (1H, d, J=8.7), 7.54 (1H, ddd,J=8.7, 6.8, 1.1), 8.39 (1H, dd, J=8.0, 1.1)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.91, 14.06, 22.68, 27.85, 29.12, 29.78, 31.26, 31.73, 49.71, 115.46,117.21, 123.86, 123.94, 126.69, 132.47, 140.53, 154.22, 169.35, 176.57

Production Example 6

<Production of the Compound Expressed by Structural Formula (1)>

In the following manner, the compound expressed by the above StructuralFormula (1) was produced through chemical synthesis.

—Production of the compound expressed by Structural Formula (1)—

The compound expressed by the above Structural Formula (21) (100 mg,0.37 mmol) was dissolved in N,N-dimethylformamide (hereinafter may bereferred to as “DMF”, 5 mL), and potassium carbonate (332 mg, 2.40 mmol)and methyl bromoacetate (53.0 mL, 0.56 mmol) were added thereto,followed by stirring at 80° C. for 12 hours. The reaction was terminatedby the addition of water, and the mixture was extracted with ethylacetate. The organic layer was dried with Glauber's salt, and then thesolvent was evaporated. The residue was purified through silica gelchromatography (hexane:ethyl acetate=2:1), and as a result the compoundexpressed by Structural Formula (1) (83.0 mg, 66%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (1) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₂₉O₃N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 344.2221 (M+H)⁺.

Calcd: 344.2220 (as C₂₁H₃₀O₃N).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2953, 2925, 2854, 1765, 1618, 1596, 1437, 1123, 968,768, 680

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.6), 1.20-1.48 (10H, m), 1.71 (2H, m), 2.43 (3H, s),2.95 (2H, m), 3.86 (3H, s), 4.62 (2H, s), 7.47 (1H, ddd, J=8.2, 6.8,1.1), 7.62 (1H, ddd, J=8.4, 6.8, 1.3), 8.00 (1H, d, J=8.4), 8.05 (1H, d,J=8.2)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.90, 14.08, 22.63, 28.99, 29.23, 29.49, 29.86, 31.83, 37.02, 52.32,70.26, 120.85, 120.73, 121.39, 121.76, 125.73, 128.82, 128.85, 147.84,159.03, 164.32, 168.95

Production Example 7

<Production of the Compound Expressed by Structural Formula (2)>

In the following manner, the compound expressed by the above StructuralFormula (2) was produced through chemical synthesis.

—Production of the compound expressed by Structural Formula (2)—

The compound expressed by the above Structural Formula (1) (80.0 mg,0.233 mmol) was dissolved in a solvent mixture of EtOH (1 mL) and THF (1mL), and sodium hydroxide aqueous solution (2 M) (0.5 ml) was addedthereto, followed by stirring at room temperature for 2 hours. The pH ofthe mixture was adjusted to 4 by the addition of 1N hydrochloric acid inan ice bath, and the mixture was extracted with ethyl acetate. Theorganic layer was dried with Glauber's salt and the solvent wasevaporated, and as a result the compound expressed by Structural Formula(2) (68.2 mg, 88%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (2) as follows.

(1) Appearance: white powder

(2) Melting point: 59° C.-62° C.

(3) Molecular formula: C₂₀H₂₇O₃N

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 330.2064 (M+H)⁺.

Calcd: 330.2064 (as C₂₀H₂₈O₃N).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2927, 2855, 2713, 1736, 1642, 1589, 1227, 1181,1078, 764, 724

(6) Proton nuclear magnetic resonance spectrum (600 MHz, Methanol-d₄):

δ=0.88 (3H, t, J=6.8), 1.25-1.41 (8H, m), 1.50 (2H, m), 1.78 (2H, m),2.54 (3H, s), 3.15 (2H, t, m), 4.92 (2H, s), 7.54 (1H, ddd, J=8.2, 7.2,1.0), 7.92 (1H, ddd, J=8.5, 6.8, 1.0), 8.07 (1H, brd, J=8.5), 8.42 (1H,brd, J=8.2)

(7) ¹³C nuclear magnetic resonance spectrum (150 MHz, Methanol-d₄):

δ=12.23, 14.40, 23.67, 29.93, 30.27, 30.34, 30.74, 32.97, 35.07, 72.72,122.81, 123.71, 123.85, 124.62, 129.16, 133.85, 142.14, 164.30, 167.46,171.91

Production Example 8

<Production of the Compound Expressed by Structural Formula (7)>

In the following manner, the compound expressed by the above StructuralFormula (7) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (7)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (21) (50.0 mg, 0.184 mmol) was dissolved in THF (1.0 mL), andlithium t-butoxide (29.4 mg, 0.37 mmol) was added thereto, followed bystirring at room temperature for 20 minutes. Next, cyanogen bromide (0.6mL, 1.84 mmol) was added thereto, and the mixture was stirred at roomtemperature for 2 hours. The reaction was terminated by the addition ofwater, and the mixture was extracted with ethyl acetate. The organiclayer was dried with Glauber's salt, and then the solvent wasevaporated. The residue was purified through silica gel chromatography(hexane:ethyl acetate=2:1), and as a result the compound expressed byStructural Formula (7) (34.0 mg, 62%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (7) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₁₉H₂₄ON₂

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 297.1961 (M+H)⁺.

Calcd: 297.1961 (as C₁₉H₂₅ON₂).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2961, 2926, 2853, 2237, 1628, 1576, 1470, 1292,1191, 761, 693

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.8), 1.20-1.50 (10H, m), 1.71 (2H, m), 2.15 (3H, s),2.93 (2H, m), 7.47 (1H, m), 7.73 (2H, m), 8.33 (1H, ddd, J=8.0, 0.92,1.1)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.20, 14.05, 22.59, 28.00, 29.07, 29.11, 29.42, 31.73, 31.80, 106.42,116.28, 120.30, 123.35, 126.23, 127.08, 133.34, 137.25, 146.10, 177.31

Production Example 9

<Production of the Compound Expressed by Structural Formula (9)>

In the following manner, the compound expressed by the above StructuralFormula (9) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (9)—

The compound expressed by the above Structural Formula (6) (100 mg, 0.30mmol) was suspended in THF (5 mL), and triethylamine (50.8 mL, 0.36mmol), diphenylphosphoryl azide (hereinafter may be referred to as“DPPA”, 72.0 mL, 0.33 mmol), and sodium thiomethoxide (23.0 mg, 0.334mmol) were added thereto, and the mixture was stirred under reflux for 2hours. Ammonium chloride aqueous solution was added thereto, and themixture was extracted with ethyl acetate. The organic layer was driedwith Glauber's salt, and the solvent was evaporated. The residue waspurified through silica gel chromatography (hexane:ethyl acetate=3:1),and as a result the compound expressed by Structural Formula (9) (39.3mg, 36%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (9) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₂₉O₂N S

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 360.1994 (M+H)⁺.

Calcd: 360.1992 (as C₂₁H₃₀O₂NS).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2924, 2852, 1687, 1614, 1594, 1542, 1193, 1028, 757,558

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.88 (3H, t, J=6.4), 1.20-1.50 (10H, m), 1.60 (2H, br), 2.23 (3H, s),2.33 (3H, s), 2.51-2.99 (2H, br), 5.01 (2H, br), 7.21 (1H, d, J=8.7),7.34 (1H, dd, J=8.0, 6.6), 7.58 (1H, ddd, J=8.7, 6.6, 1.4), 8.47 (1H,dd, J=8.0, 1.4)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.38, 11.68, 14.06, 22.60, 28.16, 29.13, 29.16, 29.75, 31.03, 31.74,55.95, 114.61, 117.94, 123.32, 127.29, 131.97, 132.02, 140.73, 150.65,177.49, 196.82

Production Example 10

<Production of the Compound Expressed by Structural Formula (10)>

In the following manner, the compound expressed by the above StructuralFormula (10) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (10)—

The compound expressed by the above Structural Formula (6) (100 mg, 0.30mmol) was suspended in THF (5 mL), and triethylamine (50.8 mL, 0.365mmol) and DPPA (72.0 mL, 0.33 mmol) were added thereto under coolingwith ice, and the mixture was further stirred under reflux for 1 hour.Sodium thiomethoxide (23.0 mg, 0.33 mmol) was added thereto, followed bystirring for another 1 hour. Ammonium chloride aqueous solution wasadded thereto, and the mixture was extracted with ethyl acetate. Theorganic layer was dried with Glauber's salt, and the solvent wasevaporated. The residue was purified through silica gel chromatography(hexane:ethyl acetate=5:1), and as a result the compound expressed byStructural Formula (10) (48.6 mg, 43%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (10) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₂₁H₃₀O₂N₂S

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 397.1921 (M+Na)⁺.

Calcd: 397.1920 (as C₂₁H₃₀O₂N₂NaS).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3169, 2955, 2927, 1671, 1615, 1595, 1556, 1492,1195, 1084, 760, 651

(5) Proton nuclear magnetic resonance spectrum (600 MHz, CDCl₃):

δ=0.89 (3H, t, J=6.7), 1.22-1.45 (15H, m), 2.45 (2H, br), 2.46 (3H, s),5.67 (2H, br), 7.24 (1H, ddd, J=7.9, 6.8, 1.0), 7.49 (1H, d, J=8.6),7.59 (1H, ddd, J=8.6, 6.8, 1.4), 8.26 (1H, dd, J=7.9, 1.4), 8.78 (1H,br)

(6) ¹³C nuclear magnetic resonance spectrum (150 MHz, CDCl₃):

δ=11.05, 12.22, 14.02, 22.59, 28.48, 29.11, 29.16, 29.73, 30.73, 31.77,52.58, 115.46, 117.00, 123.24, 124.37, 126.89, 132.32, 139.56, 151.60,168.61, 177.27

Production Example 11

<Production of the Compound Expressed by Structural Formula (11)>

In the following manner, the compound expressed by the above StructuralFormula (11) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (15)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (14) (1 equivalent) was dissolved in methylene chloride, andtriethylamine (2 equivalents) was added thereto. Furthermore, octanoylchloride (3.0 equivalents), which is an acid chloride, was addeddropwise to the mixture in an ice bath, followed by stirring at roomtemperature. The reaction was terminated with 0.1N hydrochloric acid,and the mixture was extracted with methylene chloride, followed bywashing with saturated sodium hydrogencarbonate aqueous solution andbrine. The combined organic layer was dried with Glauber's salt, andthen the solvent was evaporated. The residue was purified through silicagel chromatography (hexane:ethyl acetate), and as a result the compoundexpressed by Structural Formula (15) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (15) as follows.

(1) Appearance: colorless oily substance

(2) Molecular formula: C₁₇H₂₅O₂N

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 298.1777 (M+Na)⁺.

Calcd: 298.1778 (as C₁₇H₂₅O₂NNa).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3255, 2954, 2928, 1698, 754

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.87 (3H, t, J=6.6), 1.20-1.41 (11H, m), 1.74 (2H, m), 2.43 (2H, t,J=7.5), 3.08 (2H, q, J=7.1), 7.09 (1H, ddd, J=8.2, 7.1, 1.4), 7.53 (1H,ddd, J=8.4, 7.1, 1.4), 7.92 (1H, dd, J=8.2, 1.4), 8.77 (1H, dd, J=8.4,1.4), 11.65 (1H, br)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=8.44, 14.05, 22.59, 25.53, 28.98, 29.16, 31.67, 33.13, 38.78, 120.83,121.37, 122.11, 130.56, 134.82, 141.06, 172.78, 205.36

—Production of the Compound Expressed by Structural Formula (20)—

Sodium hydroxide (3.0 equivalents) was added to a dioxane solution ofthe compound expressed by the above Structural Formula (15) (1equivalent) (0.1 M), and the mixture was stirred at 110° C. for 1 hourto 2 hours. The reaction solution was returned to room temperature,followed by addition of water, and also, 1N hydrochloric acid was addedthereto until the pH thereof reached 7. Furthermore, when hexane wasadded and ultrasonic waves were applied thereto, solids precipitated.The solids were filtrated through aspiration, followed by washingsequentially with water and hexane. The washing was followed by drying,and as a result the compound expressed by Structural Formula (20) wasobtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (20) as follows.

(1) Appearance: white powder

(2) Melting point: 228° C.-231° C.

(3) Molecular formula: C₁₇H₂₃ON

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 258.1853 (M+H)⁺.

Calcd: 258.1852 (as C₁₇H₂₄ON).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3061, 2954, 2925, 1637, 1608, 1556, 1504, 1188, 998,754, 692

(6) Proton nuclear magnetic resonance spectrum (400 MHz, Methanol-d₄):

δ=0.88 (3H, t, J=6.6), 1.30-1.46 (8H, m), 1.65-1.73 (2H, m), 2.14 (3H,s), 2.78 (2H, t, J=7.7), 7.32 (1H, t, J=8.1), 7.52 (1H, d, m), 7.61 (1H,m), 8.21 (1H, d, J=8.2)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, Methanol-d₄):

δ=10.84, 14.40, 23.68, 29.99, 30.16, 30.54, 32.91, 33.45, 116.16,118.67, 124.38, 124.51, 126.15, 132.65, 140.55, 153.37, 179.53

—Production of the Compound Expressed by Structural Formula (11)—

In an argon atmosphere, the compound expressed by the above StructuralFormula (20) (1.0 g, 3.89 mmol) was dissolved in THF (10 mL), and a THFsolution of lithium t-butoxide (5.8 mL, 5.80 mmol) was added thereto,followed by stirring at room temperature for 20 minutes. Chloromethylthiocyanate (6.7 mL, 38.9 mmol) was added dropwise thereto under coolingwith ice, followed by further stirring at room temperature for 2 hours.The reaction was terminated by the addition of brine, and the mixturewas extracted with ethyl acetate. The organic layer was dried withGlauber's salt, and then the residue was purified through silica gelchromatography (hexane:ethyl acetate=2:1), and as a result the compoundexpressed by Structural Formula (11) (330 mg, 26%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (11) as follows.

(1) Appearance: yellow oily substance

(2) Molecular formula: C₁₉H₂₄ON₂S

(3) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 329.1682 (M+H)⁺.

Calcd: 329.1682 (as C₁₉H₂₅ON₂S).

(4) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2961, 2926, 2853, 2237, 1628, 1576, 1470, 1292,1191, 987, 761, 693

(5) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.90 (3H, t, J=6.6), 1.23-1.71 (10H, m), 2.19 (3H, s), 2.84 (2H, m),5.71 (2H, s), 7.38 (1H, ddd, J=8.0, 6.8, 0.9), 7.46 (1H, d, J=8.7), 7.68(1H, ddd, J=8.7, 6.8, 1.6), 8.45 (1H, dd, J=8.0, 1.6)

(6) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.60, 14.05, 22.56, 28.59, 28.88, 29.76, 30.55, 31.66, 56.26, 114.42,118.19, 123.83, 124.60, 127.31, 132.41, 139.86, 141.68, 149.60, 177.64

Production Example 12

<Production of the Compound Expressed by Structural Formula (12)>

In the following manner, the compound expressed by the above StructuralFormula (12) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (12)—

Acetonitrile (1.5 mL) was added to a mixture of the compound expressedby the above Structural Formula (11) (100 mg, 0.30 mmol) and sodiumthiomethoxide (23.4 mg, 0.33 mmol), followed by stirring at roomtemperature for 20 minutes. Saturated sodium hydrogencarbonate aqueoussolution was added thereto, and the mixture was extracted with ethylacetate. The organic layer was dried with Glauber's salt, and then theresidue was purified through silica gel chromatography (hexane:ethylacetate=2:1), and as a result the compound expressed by StructuralFormula (12) (31.7 mg, 27%) was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (12) as follows.

(1) Appearance: yellow powder

(2) Melting point: 167° C.-170° C.;

(3) Molecular formula: C₂₀H₂₈ON₂S₂

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 399.1534 (M+Na)⁺.

Calcd: 399.1535 (as C₂₀H₂₈ON₂NaS₂).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 3119, 2958, 2918, 2850, 1619, 1598, 1538, 1282,1199, 1105, 938, 764, 688

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.86 (3H, t, J=6.6), 1.21-1.50 (13H, m), 2.22-2.58 (2H, br), 2.76 (3H,s), 5.68-6.41 (2H, br), 7.22 (1H, t, J=7.8), 7.44 (1H, d, J=8.7), 7.59(1H, ddd, J=8.7, 7.8, 1.1), 8.15 (1H, d, J=7.8), 10.09 (1H, br)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=10.74, 14.02, 18.01, 22.53, 28.29, 28.77, 29.64, 30.85, 31.59, 58.21,115.93, 116.84, 123.54, 123.91, 126.35, 132.65, 139.39, 152.23, 177.13,199.84

Production Example 13

<Production of the Compound Expressed by Structural Formula (13)>

In the following manner, the compound expressed by the above StructuralFormula (13) was produced through chemical synthesis.

—Production of the Compound Expressed by Structural Formula (13)—

Acetonitrile (1.5 mL) was added to a mixture of the compound expressedby the above Structural Formula (11) (50.0 mg, 0.15 mmol) and sodiumthiomethoxide (10.6 mg, 0.15 mmol), followed by stirring at roomtemperature for 20 minutes. Methyl iodide (8.5 mL, 0.17 mmol) was addedthereto at room temperature, and the mixture was further stirred for 30minutes. Saturated sodium hydrogencarbonate aqueous solution was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was dried with Glauber's salt, and then the residue is purifiedthrough silica gel chromatography (hexane:ethyl acetate=2:1), and as aresult the compound expressed by Structural Formula (13) (30.6 mg, 51%)was obtained.

——Physico-Chemical Properties——

Physico-chemical properties of the compound expressed by StructuralFormula (13) as follows.

(1) Appearance: white powder

(2) Melting point: 92° C.-94° C.

(3) Molecular formula: C₂₁H₃₀ON₂S₂

(4) High resolution mass spectrometry (HRESI-MS)(m/z):

Found: 413.1689 (M+Na)⁺.

Calcd: 413.1692 (as C₂₁H₃₀ON₂NaS₂).

(5) Infrared absorption spectrum:

Peaks of infrared absorption measured by the KBr tablet method are asfollows.

ν_(max) (KBr) cm⁻¹: 2958, 2922, 2852, 1618, 1595, 1566, 1492, 1370,1277, 1192, 1004, 769, 700

(6) Proton nuclear magnetic resonance spectrum (400 MHz, CDCl₃):

δ=0.89 (3H, t, J=6.8), 1.24-1.50 (8H, m), 1.64 (2H, m), 2.22 (3H, s),2.28 (3H, s), 2.71 (3H, s), 2.77 (2H, m), 5.60 (2H, s), 7.31 (2H, m),7.55 (1H, ddd, J=8.4, 7.1, 1.6), 8.46 (1H, dd, J=8.0, 1.6)

(7) ¹³C nuclear magnetic resonance spectrum (100 MHz, CDCl₃):

δ=11.50, 14.06, 14.75, 15.03, 22.61, 28.28, 28.92, 29.83, 30.66, 31.76,63.75, 115.84, 116.97, 122.77, 124.81, 126.75, 131.27, 141.06, 151.35,161.39, 177.54

Test Example 1: Anti-Cancer Activity In Vitro

The compounds expressed by Structural Formulas (1) to (13) obtained inthe above Production Examples 1 to 13 were tested for anti-canceractivity In vitro in the following manner.

<Cell Proliferation Test 1 (Human Stomach Cancer Cells MKN-74)>

—Preparation of Cells—

Human stomach cancer cells MKN-74 (Riken Cell Bank) were cultured at 37°C. and 5% CO₂ in DMEM supplemented with 10% FBS (product of GIBCO Co.),100 units/mL penicillin G (product of Invitrogen Co.), and 100 μg/mLstreptomycin (product of Invitrogen Co.).

The above cancer cells were allowed to undergo gene transfer of Greenfluorescence protein (GFP) expression vector, pEGFP-C1 (product of BDBiosciences Co.) using the Lipofectamine reagent (product of InvitrogenCo.), to thereby clone cells stably expressing GFP.

Normal stromal cells derived from the human stomach, Hs738 ((CRL-7869),ATCC) were cultured at 37° C. and 5% CO₂ in DMEM supplemented with 10%FBS, 100 units/mL penicillin G (product of Invitrogen Co.), 100 μg/mLstreptomycin (product of Invitrogen Co.), 5 μg/mL insulin, 5 μg/mLtransferrin (product of Wako Pure Chemical Industries Co.), 1.4 μMhydrocortisone (product of Sigma Co.), and 5 mg/mL basic-FGF (product ofPepro Tech Co.).

—Coculture Test—

The above normal stromal cells derived from the human stomach, Hs738were dispersed at 5×10⁴ cells/mL in DMEM containing 1% dialyzed serum, 5μg/mL insulin, 5 μg/mL transferrine (product of Wako Pure ChemicalIndustries Co.), and 1.4 μM hydrocortisone (product of Sigma Co.), andwere placed in a 96-well plate at 0.1 mL/well. Respective evaluationsamples (the compounds expressed by Structural Formulas (1) to (13))were added thereto at respective concentrations, followed by culturingat 37° C. and 5% CO₂ for 2 days.

Next, the above human stomach cancer cells MKN-74 were dispersed in DMEMat 5×10⁵ cells/mL, and were placed at 10 μL/well in the plate in whichthe above normal stromal cells derived from the human stomach, Hs738 hadbeen cultured, followed by further coculturing at 37° C. and 5% CO₂ for3 days.

—Monoculture Test—

Only DMEM containing 1% dialyzed serum, 5 μg/mL insulin, 5 μg/mLtransferrine (product of Wako Pure Chemical Industries Co.), and 1.4 μMhydrocortisone (product of Sigma Co.) was placed in a 96-well plate at0.1 mL/well, and respective evaluation samples (the compounds expressedby Structural Formulas (1) to (13)) were added thereto at respectiveconcentrations, followed by maintaining at 37° C. and 5% CO₂ for 2 days.

Next, the above human stomach cancer cells MKN-74 were dispersed in DMEMat 5×10⁵ cells/mL, and were placed in the above plate at 10 μL/well,followed by further coculturing at 37° C. and 5% CO₂ for 3 days.

—Measurement of Cell Proliferation Rates—

Measurement of cell proliferation rates in the above coculture test andmonoculture test was performed in the following manner.

The medium was removed from the wells of the above plate, and acytolysis liquid (10 mM Tris-HCl [pH 7.4], 150 mM NaCl, 0.9 mM CaCl₂,and 1% Triton X-100) was added thereto at 0.1 mL/well to lyse the cells.The fluorescence intensity of GFP was measured at an excitationwavelength of 485 nm and a fluorescence wavelength of 538 nm, and thecell proliferation rates were calculated from the following formula. Theresults of the cell proliferation rates were used to calculate IC₅₀, andthe calculated results are presented in Table 1.Cell proliferation rate (%)=(Fluorescence intensity in the presence ofthe evaluation sample/Fluorescence intensity in the absence of theevaluation sample)×100

TABLE 1 Mono Cocul Compounds IC₅₀ (μg/mL) IC₅₀ (μg/mL) StructuralFormula (1) 28.1 0.35 Structural Formula (2) 2.95 0.37 StructuralFormula (3) >100 0.012 Structural Formula (4) >100 1.32 StructuralFormula (5) >100 0.53 Structural Formula (6) 70.95 4.15 StructuralFormula (7) >100 0.007 Structural Formula (8) >100 >100 StructuralFormula (9) 5.84 1.4 Structural Formula (10) 7.57 0.27 StructuralFormula (11) 89.5 0.12 Structural Formula (12) 39.5 2.91 StructuralFormula (13) 1.36 0.78

The values in Table 1 are average values in duplicate, and standarderrors (SE) were 10% or less.

In Table 1, “Mono” presents the results of the monoculture test, and“Cocul” presents the results of the coculture test.

As presented in Table 1, each of the 13 compounds expressed by the aboveStructural Formulas (1) to (13) strongly inhibited proliferation of thestomach cancer cells MKN-74 cocultured with the stromal cells (Cocul) atlower concentrations (lower IC₅₀ values) as compared with the stomachcancer cells MKN-74 monocultured (Mono).

Test Example 2: Anti-Cancer Activity In Vivo

The compound expressed by Structural Formula (2) and the compoundexpressed by Structural Formula (13) obtained in the above ProductionExamples were tested for anti-cancer activity In vivo in the followingmanner.

Test Example 2-1: Human Stomach Cancer Cells MKN-74 Alone

BALB/c nu/nu nude mice (female, 5 weeks old, product of Charles RiverCo.) were bred under the SPF conditions.

Cultured human stomach cancer cells MKN-74 were trypsinized, and thehuman stomach cancer cells MKN-74 (8×10⁶ cells) peeled off from theculture dish were dispersed in 0.3 mL DMEM containing 10% FBS and mixedwith 0.5 mL growth factor-reduced Matrigel (product of BD BiosciencesCo.).

The above mixed cell liquid (0.1 mL) (cancer cells: 1×10⁶ cells) wassubcutaneously inoculated to the left groin region of the above mice.

The compound expressed by the Structural Formula (2) or the compoundexpressed by the Structural Formula (13) was intravenously administeredfor a predetermined period, and tumor formed under the skin was cut outand measured for weight. Note that, the administration dose of thecompound expressed by the Structural Formula (2) or the compoundexpressed by the Structural Formula (13) was 12.5 mg/kg peradministration day.

Also, a tumor volume was calculated from the following formula referringto the above NPL 1.Tumor volume (mm³)=(major axis×minor axis)/2

Note that, as controls, those to which physiological saline (vehicle)was administered instead of the compound expressed by the StructuralFormula (2) or the compound expressed by the Structural Formula (13)were tested in the same manner.

Test Example 2-2: Human Stomach Cancer Cells MKN-74 and Normal StromalCells Derived from the Human Stomach, Hs738

A test was performed in the same manner as in Test Example 2-1 exceptthat the use of the human stomach cancer cells MKN-74 alone in TestExample 2-1 was changed to use of the human stomach cancer cells MKN-74and the normal stromal cells derived from the human stomach, Hs738.

Note that, a cell liquid and inoculation of the cell liquid to mice wereas follows.

Cultured human stomach cancer cells MKN-74 and normal stromal cellsderived from the human stomach, Hs738 were respectively trypsinized tobe peeled off from the culture dishes. The above human stomach cancercells MKN-74 (8×10⁶ cells) and the above normal stromal cells derivedfrom the human stomach, Hs738 (8×10⁶ cells) were dispersed in 0.3 mLDMEM containing 10% FBS and mixed with 0.5 mL growth factor-reducedMatrigel (product of BD Biosciences Co.).

The above mixed cell liquid (0.1 mL) (a mixture of cancer cells: 1×10⁶cells, and stromal cells: 1×10⁶ cells) was subcutaneously inoculated tothe left groin region of the above mice.

The results of the above Test Example 2 are presented in FIGS. 1A to 1D.

FIG. 1A indicates changes in tumor volume in Test Example 2-1, FIG. 1Bindicates changes in tumor weight in Test Example 2-1 (Day 21 frominoculation of tumor), FIG. 1C indicates changes in tumor volume in TestExample 2-2, and FIG. 1D indicates changes in tumor weight in TestExample 2-2 (Day 21 from inoculation of tumor).

In FIGS. 1A and 1C, “white circle” indicates the results of “vehicle”,“black circle” indicates the results obtained “when the administrationdose of the compound expressed by Structural Formula (2) was 12.5mg/kg”, and “white square” indicates the results obtained “when theadministration dose of the compound expressed by Structural Formula (13)was 12.5 mg/kg”. Also, in FIGS. 1A and 1C, “arrow” indicates the daywhen the compound expressed by Structural Formula (2) or the compoundexpressed by Structural Formula (13) was administered.

FIGS. 1B and 1D, “white” indicates the results of “vehicle”, “black”indicates the results obtained “when the administration dose of thecompound expressed by Structural Formula (2) was 12.5 mg/kg”, and “gray”indicates the results obtained “when the administration dose of thecompound expressed by Structural Formula (13) was 12.5 mg/kg”.

The values in FIGS. 1A to 1D are average values in 5 mice and standarddeviations (SD), and * indicates P<0.05 and ** indicates P<0.01.

As presented in FIGS. 1A to 1D, in the case of the human stomach cancercells MKN-74 alone, significant suppression was observed by intravenousadministration of the compound expressed by Structural Formula (2) at12.5 mg/kg.

Meanwhile, in the case of the tumor transplanted together with thenormal stromal cells derived from the human stomach, Hs738, significantsuppression was observed by intravenous administration of the compoundexpressed by Structural Formula (13) at 12.5 mg/kg.

Test Example 3: Acute Toxicity Test

ICR mice (female, 4 weeks old, product of Charles River Co.) were bredunder the SPF conditions.

As evaluation samples, the compounds expressed by the above StructuralFormulas (1) to (13) were intravenously administered thereto, and themice were observed for 2 weeks. One half of the administration dose atwhich the mice were recognized to be dead or have serious toxicity forthe observation period of 2 weeks was defined as the maximum tolerateddose (MTD) in the present experiment. The results are presented in Table2.

TABLE 2 MTD Compounds (mg/kg) Structural Formula (1) >50.0 StructuralFormula (2) >50.0 Structural Formula (3) 1.56 Structural Formula (4) 25Structural Formula (5) 6.25 Structural Formula (6) >50.0 StructuralFormula (7) 6.25 Structural Formula (8) 12.5 Structural Formula(9) >50.0 Structural Formula (10) >50.0 Structural Formula (11) 6.25Structural Formula (12) >50.0 Structural Formula (13) >50.0

From the results of the above Table 2, the MTD was found to be 50 mg/kgor higher when the compound expressed by the above Structural Formula(1), the compound expressed by the above Structural Formula (2), thecompound expressed by the above Structural Formula (6), the compoundexpressed by the above Structural Formula (9), the compound expressed bythe above Structural Formula (10), the compound expressed by the aboveStructural Formula (12), and the compound expressed by the aboveStructural Formula (13) were intravenously administered.

Test Example 4: Anti-Bacterial Activity

The compound expressed by the above Structural Formula (2), the compoundexpressed by the above Structural Formula (3), the compound expressed bythe above Structural Formula (4), the compound expressed by the aboveStructural Formula (5), the compound expressed by the above StructuralFormula (6), the compound expressed by the above Structural Formula (8),the compound expressed by the above Structural Formula (11), thecompound expressed by the above Structural Formula (12), and thecompound expressed by the above Structural Formula (13) were tested foranti-bacterial activity in the following manner.

Note that, as comparisons, clarithromycin and ampicillin (ABPC) weretested in the same manner.

Test Example 4-1: Measurement of MIC for Helicobacter pylori

Each of the above compounds was measured for minimum inhibitoryconcentration (MIC) for Helicobacter pylori.

Helicobacter pylori JCM12093 strain and H. pylori JCM12095 strain eachwere statically cultured in a HP medium (brain heart infusion broth(product of Becton, Dickinson Co.) supplemented with 10% fetal bovineserum (product of Life Technologies Co.)) for 144 hours at 37° C. undermicroaerobic culture conditions (microaerobic conditions(N₂:O₂:CO₂=85:5:10)).

After completion of the culturing, the culture was suspended with the HPmedium and diluted so that Helicobacter pylori was 2×10⁶ CFU/mL to 9×10⁶CFU/mL.

Each of the test samples (each of the above compounds, clarithromycin,and ampicillin) was prepared with the HP medium to have a concentrationof 256 mg/L. From this concentration, the test sample was 2-fold dilutedserially in 15 steps to 0.0078 mg/L.

The above-diluted culture was added at 50 μL/well to 50 μL/well of theHP medium containing each of the test samples at the aboveconcentrations, and was statically cultured for 144 hours at 37° C.under microaerobic culture conditions (microaerobic conditions(N₂:O₂:CO₂=85:5:10)). After completion of the culturing, the presence orabsence of proliferation of each bacterium was visually determined basedon turbidity, and the MIC for each bacterial strain was obtained. Theresults are presented in Table 3.

Test Example 4-2: Measurement of MIC for Staphylococcus aureus andEscherichia coli

Each of the above compounds was measured for minimum inhibitoryconcentration (MIC) for Staphylococcus aureus and Escherichia coli.

Staphylococcus aureus FDA209P strain and Escherichia coli K-12 straineach were cultured under shaking in a nutrient broth medium (polypeptone(product of NIHON PHARMACEUTICAL Co.) 1%, fish extract for bacteria(product of KYOKUTO PHARMACEUTICAL INDUSTRIAL Co.) 1%, and sodiumchloride 0.2%) at 37° C. overnight.

After completion of the culturing, the culture was diluted with thenutrient broth medium so that the bacteria were 2×10⁶ CFU/mL to 9×10⁶CFU/mL.

Each of the test samples (each of the above compounds, clarithromycin,and ampicillin) was prepared with the nutrient broth medium to have aconcentration of 256 mg/L. From this concentration, the test sample was2-fold diluted serially in 11 steps to 0.125 mg/L.

The above-diluted culture was added at 50 μL/well to 50 μL/well of thenutrient broth medium containing each of the test samples at the aboveconcentrations, and was statically cultured at 37° C. overnight. Aftercompletion of the culturing, the presence or absence of proliferation ofeach bacterium was visually determined based on turbidity, and the MICfor each bacterial strain was obtained. The results are presented inTable 3.

Test Example 4-3: Measurement of MIC for Enterococcus faecalis

Each of the above compounds was measured for minimum inhibitoryconcentration (MIC) for Enterococcus faecalis.

Enterococcus faecalis JCM5803 strain was cultured under shaking in aheart infusion broth medium (product of Becton, Dickinson Co.) at 37° C.overnight.

After completion of the culturing, the culture was diluted with theheart infusion broth medium so that the bacteria were 2×10⁴ CFU/mL to9×10⁴ CFU/mL.

Each of the test samples (each of the above compounds, clarithromycin,and ampicillin) was prepared with the heart infusion broth medium tohave a concentration of 256 mg/L. From this concentration, the testsample was 2-fold diluted serially in 11 steps to 0.125 mg/L.

The above-diluted culture was added at 50 μL/well to 50 μL/well of theheart infusion broth medium containing each of the test samples at theabove concentrations, and was statically cultured at 37° C. for 18hours.

After completion of the culturing, the presence or absence ofproliferation of each bacterium was visually determined based onturbidity, and the MIC for each bacterial strain was obtained. Theresults are presented in Table 3.

Test Example 4-4: Measurement of MIC for Haemophilus influenzae

Each of the above compounds was measured for minimum inhibitoryconcentration (MIC) for Haemophilus influenzae.

Haemophilus influenzae T-196 strain and H. influenzae ARD476 strain eachwere statically cultured in a HI medium (Muller Hinton medium (productof Becton, Dickinson Co.) supplemented with 5% Fildes enrichment(product of Becton, Dickinson Co.)) at 37° C. overnight under aerobicconditions containing 5% carbon dioxide gas.

After completion of the culturing, the culture was suspended with the HImedium and diluted so that each Haemophilus influenza strain was 2×10⁶CFU/mL to 9×10⁶ CFU/mL.

Each of the test samples (each of the above compounds, clarithromycin,and ampicillin) was prepared with the HI medium to have a concentrationof 256 mg/L. From this concentration, the test sample was 2-fold dilutedserially in 11 steps to 0.125 mg/L.

The above-diluted culture was added at 50 μL/well to 50 μL/well of theHI medium containing each of the test samples at the aboveconcentrations, and was statically cultured for 18 hours at 37° C. underaerobic conditions containing 5% carbon dioxide gas.

After completion of the culturing, the presence or absence ofproliferation of each bacterium was visually determined based onturbidity, and the MIC for each bacterial strain was obtained. Theresults are presented in Table 3.

TABLE 3 Helicobacter Staphylococcus Enterococcus Escherichia HaemophilusMIC pylori H. pylori aureus faecalis coli influenzae H. influenzae(μg/ml) JCM 12093 JCM 12095 FDA209P JCM5803 K-12 T-196 ARD476 Structural1 0.5 >128 >128 128 64 64 Formula (2) Structural 0.0080.016 >128 >128 >128 >128 >128 Formula (3) Structural 0.5 0.25 128 >128128 64 128 Formula (4) Structural 2 2 >128 >128 >128 >128 >128 Formula(5) Structural 1 0.25 128 >128 128 128 128 Formula (6) Structural 10.5 >128 >128 >128 64 64 Formula (8) Structural 0.016 0.0164 >128 >128 >128 >128 Formula (11) Structural 0.030.06 >128 >128 >128 >128 >128 Formula (12) Structural 2 24 >128 >128 >128 >128 Formula (13) Clarithromycin 0.008 0.008 <0.125 0.516 8 4 ABPC 0.25 0.13 <0.125 0.5 4 0.5 64

As presented in Table 3, each of the above compounds exhibitedanti-Helicobacter pylori activity. Among them, the compound expressed byStructural Formula (3), the compound expressed by Structural Formula(11), and the compound expressed by Structural Formula (12) exhibitedanti-Helicobacter pylori activity at low concentrations.

Meanwhile, each of the above compounds exhibited low anti-bacterialactivity against other general bacteria causing infectious diseases.

INDUSTRIAL APPLICABILITY

Since the compounds expressed by Structural Formulas (1) to (13) of thepresent invention have excellent anti-cancer effects, or excellentanti-Helicobacter pylori activity, and are highly safe compounds, theycan be suitably used as an active ingredient of a pharmaceuticalcomposition, an anti-cancer agent, an anti-Helicobacter pylori agent,and the like.

The invention claimed is:
 1. A method for producing a compound expressedby Structural Formula (1) below, the method comprising: reacting acompound expressed by Structural Formula (21) below with a carbonic acidsalt of an alkali metal or a hydride of an alkali metal, or boththereof, and methyl bromoacetate:

where in the Structural Formula (1), Me denotes a methyl group.
 2. Amethod for producing a compound expressed by Structural Formula (2)below, the method comprising: reacting a compound expressed byStructural Formula (1) below with a hydroxide of an alkali metal or ahydroxide of an alkaline earth metal, or both thereof, to thereby obtaina reaction product, and acidifying a pH of the reaction product:

where in the Structural Formula (1), Me denotes a methyl group.